内质网应激介导糖皮质激素免疫刺激作用及其分子机制
|
摘要
感染是严重创伤常见并发症,目前对其救治仍缺乏有效的措施。因此,在创伤早期预防和治疗损伤诱发的器官功能不全具有十分重要的意义。创伤可导致免疫反应异常,而这与创伤后严重感染易感性增加有关。神经内分泌反应是创伤后最早出现的一种机体反应。大量研究表明神经内分泌系统对免疫功能具有重要的调控作用。严重创伤后,下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴激活是创伤早期主要的神经内分泌反应。糖皮质激素(glucocorticoids, GCs)是HPA轴的最终效应激素,对免疫系统具有重要调控作用。因GCs具有广泛而重要的免疫抑制特性,被临床上作为抗炎药物。大量研究表明,除了免疫抑制作用外,内源性或天然GCs也可产生免疫刺激作用。本课题组前期研究表明一定剂量的内源性GCs (皮质酮)可增强巨噬细胞免疫功能。然而,对于GCs免疫刺激作用的机制尚不清楚。
内质网是参与钙调节和蛋白折叠的一种重要细胞器,对维持细胞内稳态十分重要。一旦内质网内稳态受各种应激干扰而发生紊乱,新合成的未折叠蛋将在内质网腔内蓄积,诱发内质网应激(endoplasmic reticulum stress,ERS)。为应对蓄积的未折叠蛋白,哺乳动物细胞可触发一种特异的适应性反应,即未折叠蛋白反应(unfolded protein response,UPR),UPR对ERS时细胞恢复,以及活跃的分泌细胞(如免疫细胞)的功能与存活相当重要。巨噬细胞广泛分布于哺乳动物组织,在天然免疫和获得性免疫中起重要作用。近年来研究发现免疫细胞发生ERS在细胞功能调控中起重要作用,如抗原提呈、浆细胞分化、抗体生成以及T细胞对抗原反应等。另外,也有大量研究表明ERS与免疫炎症反应关系密切。ERS相关的转录因子X盒结合蛋白1(X-box binding protein 1, XBP1)和激活转录因子6 (activating transcription factor 6, ATF6)在ERS诱导细胞功能变化中具有重要作用。然而,GCs对巨噬细胞ERS的影响及其与GCs免疫刺激作用的关系目前尚未明确。
基于本课题组前期研究发现及目前研究现状,我们推测ERS可能在介导GCs免疫刺激中具有重要作用。由此,本课题主要围绕GCs免疫刺激作用与免疫细胞ERS的关系及其可能的分子机制,分别从四个方面进行了系统研究:(1)应用不同浓度内源性GCs (皮质酮)处理小鼠腹腔巨噬细胞,观察ERS相关分子GRP78、XBP1和ATF6表达变化,首先明确GCs对巨噬细胞ERS的诱导作用。为了进一步阐明ERS与免疫功能变化之间的关系,我们观察了ERS诱导剂毒胡萝卜素对小鼠腹腔巨噬细胞免疫功能的影响。此外,对GCs免疫抑制作用与ERS的关系进行了研究。(2)应用CRH基因敲除小鼠,观察急性束缚应激后HPA轴活性对免疫细胞ERS的影响及其与免疫功能变化的关系。(3)应用慢病毒介导的RNA干扰技术,通过选择性沉默小鼠XBP1基因,观察XBP1在低浓度皮质酮免疫刺激中的作用。(4)应用GR拮抗剂RU486,观察低浓度皮质酮诱导ERS与GR的关系。通过上述系统性研究,明确ERS介导GCs免疫刺激的作用及其分子机制,为深入阐明神经内分泌系统对免疫功能的调控提供实验依据。
主要结果如下:
1.前期研究提示低浓度GCs对巨噬细胞有免疫刺激作用。为了检测GCs诱导小鼠腹腔巨噬细胞内质网应激的作用,以及明确ERS在低浓度GCs诱导免疫刺激中的作用。我们应用不同浓度皮质酮(啮齿动物的主要内源性GCs)处理小鼠腹腔巨噬细胞,观察GCs诱发ERS的作用,同时,检测UPR信号通路中两个重要的转录因子XBP1和ATF6的表达。结果发现,低浓度皮质酮(10 ng/ml and 50 ng/ml)诱导小鼠腹腔巨噬细胞ERS同时,可激活UPR,并且观察到XBP1 mRNA发生剪接和ATF6蛋白分解。为了进一步明确ERS与巨噬细胞免疫变化之间的关系,我们观察了ERS诱导剂毒胡萝卜素对巨噬细胞免疫功能的影响。结果显示,与低浓度皮质酮的免疫刺激作用一样,毒胡萝卜素可增强巨噬细胞趋化、吞噬功能及TNF-α生成。并且,高浓度皮质酮(1000 ng/ml)对LPS刺激的小鼠巨噬细胞(RAW264.7细胞)产生免疫抑制效应的同时能抑制LPS诱导的RAW264.7细胞ERS,提示GCs免疫抑制作用也与ERS有关。
2.促肾上腺皮质素释放激素(Corticotropin-releasing hormone,CRH)是HPA轴最近端的应激激素,是应激时神经内分泌反应的中枢性协调分子。为了进一步检测HPA轴活性对免疫细胞ERS的影响及其与免疫功能变化的关系。我们应用CRH基因敲除小鼠,观察在心理应激(束缚应激) 1 h后免疫细胞GRP78、XBP1和ATF6的表达及免疫功能的变化。结果显示,与CRH-/-小鼠相比,CRH+/+和CRH+/-小鼠在急性束缚应激后,免疫细胞GRP78的mRNA和蛋白表达水平均显著增加,同时,也观察到IRE1/XBP1和ATF6信号转导通路激活,并且,发现与CRH-/-小鼠相比,CRH+/+和CRH+/-小鼠腹腔巨噬细胞的免疫功能均显著增强。
3.观察了XBP1在GCs调控巨噬细胞功能中的作用,通过构建并筛选小鼠XBP1基因的RNA干扰慢病毒载体,应用XBP1-siRNA慢病毒感染小鼠腹腔巨噬细胞,选择性失活XBP1基因,发现低浓度皮质酮(50 ng/ml)不能增强小鼠腹腔巨噬细胞的吞噬功能及分泌TNF-α的能力。
4. GCs的活性主要是由糖皮质激素受体(glucocorticoid receptor,GR)所介导。因此,我们观察了GR在低浓度皮质酮诱导巨噬细胞ERS中的作用。结果显示,应用GR拮抗剂RU486预处理巨噬细胞能显著地抑制低浓度皮质酮(50 ng/ml)诱导的GRP78、XBP1 mRNA及蛋白表达水平的增加。此外,应用RU486阻断GR能部分抑制低浓度皮质酮的免疫刺激作用。
主要结论:
1.低浓度皮质酮可诱导巨噬细胞ERS,激活UPR。与低浓度皮质酮产生的免疫刺激作用相似,毒胡萝卜素诱导巨噬细胞内质网应激也具有免疫刺激作用。GCs免疫抑制作用也与ERS有关。总之,这些结果表明低浓度皮质酮对巨噬细胞免疫刺激作用可能与诱导细胞内ERS相关。
2.适度HPA轴活化可诱导免疫细胞ERS,增强免疫细胞功能。因而从整体水平证实内源性GCs免疫刺激作用可能与诱导免疫细胞ERS有关。
3. XBP1在调控低浓度皮质酮免疫刺激作用中具有重要作用。
4.低浓度皮质酮诱导巨噬细胞免疫刺激作用至少部分由GR所介导,而且,在巨噬细胞低浓度皮质酮是通过GR诱导ERS。
Infection is a common complication after severe trauma. there are still no effective therapeutic strategies so far. Therefore, the prevention and treatment of injury-induced organ dysfunction is very important at the early stage of injury. Major trauma results in massive impairment of immunologic reactivity, which has been demonstrated to correlate clinically with increased susceptibility to serious infection. It has been found to elicit neuroendocrine responses immediately after trauma. There is increasing evidence revealing that the neuroendocrine system is important in the regulation of immune function. The key neuroendocrine response to stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, The glucocorticoids (GCs) are the final effectors of the HPA axis. These GCs play an important role in the modulation of the immune system. GCs are regarded widely as being immunosuppressive and are used clinically as antiinflammatory agents. A growing body of literature suggests that, far from being suppressive, endogenous or natural GCs are also known to exert immunostimulatory effects. Previous study showed that GCs can enhance the immune functions of peritoneal macrophages, specially at low concentrations. However, the precise cellular mechanisms underlying the immunostimulatory effects of GCs have not been fully elucidated.
The endoplasmic reticulum (ER) is a critical organelle involved in intracellular calcium regulation and protein folding, which are crucial for cellular homeostasis. Once ER homeostasis is perturbed by various stressors, newly synthesized unfolded proteins accumulate in the ER, resulting in ER stress (ERS). To cope with accumlated unfolded ER proteins, mammalian cells trigger a specific adaptive response called the unfolded protein response (UPR). UPR is crucial both for cell recovery under condition of ERS and for the function and survival of active secretory cells, such as immune cells. Macrophages are ubiquitous in mammalian tissues and play a central role in both innate and acquired immune responses. Recently, emerging evidence indicates that ERS in immune cells has been shown to play an important role in the regulation of the cellular functions, such as antigen presentation, plasma cell differentiation and antibody production, and T cell response to antigen. In addition, there is also increasing evidence indicating a strong link between ERS and immune inflammatory response. ERS-induced transcription factors, such as X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6) have been demonstrated to play an essential role in ERS-induced changes in cellular functions. However, the effects of GCs on macrophage ERS and its relationship with the immunostimulatory effects have yet to be defined.
Based on our previous findings and current researches, the aim of this work was to investigate whether the immunostimulatory effects of GCs mediated by ERS and their potential molecular mechanisms, which includes the following four aspects: (1) To observe the expression changes of ERS-associated molecules GRP78, XBP1 and ATF6 in mice peritoneal macrophages treated with various concentrations of endogenous GCs (corticosterone). In order to further elucidate the relationship between ERS and altered immune functions, we investigated the effects of thapsigargin, an ERS inducer, on immune functions of mice peritoneal macrophages. Furthermore, to investigate the relationship the immunosuppressive effects of GCs between ERS in vitro. (2) We used CRH knockout (CRH-/-) mice, to observe in vivo the effects of the HPA axis activation on ERS and immune functions of immune cells of mice exposed to acute restraint stress. (3) Using lentiviral-mediated RNAi (RNA interference) technology, selectively silenceing of the XBP1 gene in mice, to investigate the role of XBP1 in the immunostimulatory effects of low concentration of corticosterone in vitro. (4) To use the GR antagonists RU486 (mifepristone) to explore the relationship between low concentration of corticosterone-induced ERS and GR. The purpose of this study is to further elucidate the molecular mechanisms of the immunostimulatory effects of GCs, and then provide more evidence for deepening the understanding of the regulation of the neuroendocrine system on the immune function.
The main results are shown as follows:
1. Previous works indicate that low concentrations of GCs exert immunostimulatory effects on macrophages function. In order to test the hypothesis that GCs induces ERS in mice peritoneal macrophages, and to elucidate the role of ERS in low concentrations of GCs-induced immunostimulation. We treated mice peritoneal macrophages with various concentrations of corticosterone, a major type of endogenous GCs in rodents, to observe the GCs-induced ERS. Meanwhile, we further examined the expression of XBP1 and ATF6, two key transcription factors of UPR signaling pathway. In parallel to induction of ERS, low concentrations of corticosterone (10 ng/ml and 50 ng/ml) could also activate the UPR. Splicing of XBP1 mRNA and ATF6 cleavage were observed in mice peritoneal macrophages. In order to further elucidate the relationship between ERS and altered immune functions of macrophages, we investigated the effects of thapsigargin, an ERS inducer, on macrophage function. Similar to the immunostimulatory effects of low concentrations of corticosterone, thapsigarin could enhance macrophages chemotaxis, phagocytosis and TNF-αproduction. However, high concentrations of corticosterone (1000 ng/ml) exert immunosuppressive effects on mouse macrophages (RAW264.7 cells) following stimulation with lipopolysaccharide (LPS), and inhibit LPS-induced ERS of RAW264.7 cells.
2. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine response to stress. To further examine the effects of HPA axis activation on ERS of immune cells and its relationship with altered immune functions in vivo, we investigated the expression of GRP78, XBP1 and ATF6 and altered immune functions of immune cells of CRH knockout mice exposed to the psychological stress (restraint stress) for 1 h. Our results show that following acute restraint stress, compared to CRH-/- mice, the mRNA and protein expression levels of GRP78 were significantly increaed in immune cells of CRH+/+ or CRH+/- mice. Meanwhile, IRE1/XBP1 and ATF6 signaling pathway were activated. Furthermore, we show here that the immune functions of primary peritoneal macrophages of CRH+/+ or CRH+/- mice was greatly enhanced, compared to those of CRH-/- mice.
3. To explore the role of XBP1 in modulation of macrophage functions by GCs, after construction and screening of lentiviral vector of RNA interference of mouse XBP1 gene, we selectively inactivated the XBP1 gene in mice peritoneal macrophages infected with XBP1-siRNA lentivirus. We found that low concentration of corticosterone (50 ng/ml) did not increase the cellular phagocytosis and TNF-αproduction.
4. The activities of GCs are mostly mediated by the glucocorticoid receptor (GR). Thus, we investigated the possible role of GR in the induction of ER stress in macrophages by low concentration of corticosterone. Our results showed that pretreatment of macrophages with the classical GR antagonist RU486 (mifepristone) could significantly inhibit the increased expression of GRP78 and XBP1 at both mRNA and protein levels induced by low concentration of corticosterone. Furthermore, blocking of the GR by RU486 partly abolished the immunostimulatory effects of low concentration of corticosterone.
Taken together, we concluded that:
1. In parallel to induction of ERS, low concentrations of corticosterone could also activate the UPR. Similar to the immunostimularoty effects of low concentrations of corticosterone, thapsigarin could enhance macrophages chemotaxis, phagocytosis and TNF-αproduction. high concentrations of corticosterone exert immunosuppressive effects related to ERS. Together, these results suggest that the immunostimulatory effects of low concentrations of corticosterone on macrophages might be related to its induction of intracellular ERS.
2. HPA axis activation could induce ERS and enhance immune functions of immune cells, and also highlight a mechanistic association between the moderate activation of the HPA axis elicited immunostimulatory effects and induced ERS of immune cells.
3. XBP1 might play an important role in modulation of the immunostimulatory effects of low concentration of corticosterone.
4. GR was at least partly responsible for the immunostimulatory effects of macrophages induced by low concentration of corticosterone. Furthermore, low concentration of corticosterone induces ERS via GR in macrophages.
内质网是参与钙调节和蛋白折叠的一种重要细胞器,对维持细胞内稳态十分重要。一旦内质网内稳态受各种应激干扰而发生紊乱,新合成的未折叠蛋将在内质网腔内蓄积,诱发内质网应激(endoplasmic reticulum stress,ERS)。为应对蓄积的未折叠蛋白,哺乳动物细胞可触发一种特异的适应性反应,即未折叠蛋白反应(unfolded protein response,UPR),UPR对ERS时细胞恢复,以及活跃的分泌细胞(如免疫细胞)的功能与存活相当重要。巨噬细胞广泛分布于哺乳动物组织,在天然免疫和获得性免疫中起重要作用。近年来研究发现免疫细胞发生ERS在细胞功能调控中起重要作用,如抗原提呈、浆细胞分化、抗体生成以及T细胞对抗原反应等。另外,也有大量研究表明ERS与免疫炎症反应关系密切。ERS相关的转录因子X盒结合蛋白1(X-box binding protein 1, XBP1)和激活转录因子6 (activating transcription factor 6, ATF6)在ERS诱导细胞功能变化中具有重要作用。然而,GCs对巨噬细胞ERS的影响及其与GCs免疫刺激作用的关系目前尚未明确。
基于本课题组前期研究发现及目前研究现状,我们推测ERS可能在介导GCs免疫刺激中具有重要作用。由此,本课题主要围绕GCs免疫刺激作用与免疫细胞ERS的关系及其可能的分子机制,分别从四个方面进行了系统研究:(1)应用不同浓度内源性GCs (皮质酮)处理小鼠腹腔巨噬细胞,观察ERS相关分子GRP78、XBP1和ATF6表达变化,首先明确GCs对巨噬细胞ERS的诱导作用。为了进一步阐明ERS与免疫功能变化之间的关系,我们观察了ERS诱导剂毒胡萝卜素对小鼠腹腔巨噬细胞免疫功能的影响。此外,对GCs免疫抑制作用与ERS的关系进行了研究。(2)应用CRH基因敲除小鼠,观察急性束缚应激后HPA轴活性对免疫细胞ERS的影响及其与免疫功能变化的关系。(3)应用慢病毒介导的RNA干扰技术,通过选择性沉默小鼠XBP1基因,观察XBP1在低浓度皮质酮免疫刺激中的作用。(4)应用GR拮抗剂RU486,观察低浓度皮质酮诱导ERS与GR的关系。通过上述系统性研究,明确ERS介导GCs免疫刺激的作用及其分子机制,为深入阐明神经内分泌系统对免疫功能的调控提供实验依据。
主要结果如下:
1.前期研究提示低浓度GCs对巨噬细胞有免疫刺激作用。为了检测GCs诱导小鼠腹腔巨噬细胞内质网应激的作用,以及明确ERS在低浓度GCs诱导免疫刺激中的作用。我们应用不同浓度皮质酮(啮齿动物的主要内源性GCs)处理小鼠腹腔巨噬细胞,观察GCs诱发ERS的作用,同时,检测UPR信号通路中两个重要的转录因子XBP1和ATF6的表达。结果发现,低浓度皮质酮(10 ng/ml and 50 ng/ml)诱导小鼠腹腔巨噬细胞ERS同时,可激活UPR,并且观察到XBP1 mRNA发生剪接和ATF6蛋白分解。为了进一步明确ERS与巨噬细胞免疫变化之间的关系,我们观察了ERS诱导剂毒胡萝卜素对巨噬细胞免疫功能的影响。结果显示,与低浓度皮质酮的免疫刺激作用一样,毒胡萝卜素可增强巨噬细胞趋化、吞噬功能及TNF-α生成。并且,高浓度皮质酮(1000 ng/ml)对LPS刺激的小鼠巨噬细胞(RAW264.7细胞)产生免疫抑制效应的同时能抑制LPS诱导的RAW264.7细胞ERS,提示GCs免疫抑制作用也与ERS有关。
2.促肾上腺皮质素释放激素(Corticotropin-releasing hormone,CRH)是HPA轴最近端的应激激素,是应激时神经内分泌反应的中枢性协调分子。为了进一步检测HPA轴活性对免疫细胞ERS的影响及其与免疫功能变化的关系。我们应用CRH基因敲除小鼠,观察在心理应激(束缚应激) 1 h后免疫细胞GRP78、XBP1和ATF6的表达及免疫功能的变化。结果显示,与CRH-/-小鼠相比,CRH+/+和CRH+/-小鼠在急性束缚应激后,免疫细胞GRP78的mRNA和蛋白表达水平均显著增加,同时,也观察到IRE1/XBP1和ATF6信号转导通路激活,并且,发现与CRH-/-小鼠相比,CRH+/+和CRH+/-小鼠腹腔巨噬细胞的免疫功能均显著增强。
3.观察了XBP1在GCs调控巨噬细胞功能中的作用,通过构建并筛选小鼠XBP1基因的RNA干扰慢病毒载体,应用XBP1-siRNA慢病毒感染小鼠腹腔巨噬细胞,选择性失活XBP1基因,发现低浓度皮质酮(50 ng/ml)不能增强小鼠腹腔巨噬细胞的吞噬功能及分泌TNF-α的能力。
4. GCs的活性主要是由糖皮质激素受体(glucocorticoid receptor,GR)所介导。因此,我们观察了GR在低浓度皮质酮诱导巨噬细胞ERS中的作用。结果显示,应用GR拮抗剂RU486预处理巨噬细胞能显著地抑制低浓度皮质酮(50 ng/ml)诱导的GRP78、XBP1 mRNA及蛋白表达水平的增加。此外,应用RU486阻断GR能部分抑制低浓度皮质酮的免疫刺激作用。
主要结论:
1.低浓度皮质酮可诱导巨噬细胞ERS,激活UPR。与低浓度皮质酮产生的免疫刺激作用相似,毒胡萝卜素诱导巨噬细胞内质网应激也具有免疫刺激作用。GCs免疫抑制作用也与ERS有关。总之,这些结果表明低浓度皮质酮对巨噬细胞免疫刺激作用可能与诱导细胞内ERS相关。
2.适度HPA轴活化可诱导免疫细胞ERS,增强免疫细胞功能。因而从整体水平证实内源性GCs免疫刺激作用可能与诱导免疫细胞ERS有关。
3. XBP1在调控低浓度皮质酮免疫刺激作用中具有重要作用。
4.低浓度皮质酮诱导巨噬细胞免疫刺激作用至少部分由GR所介导,而且,在巨噬细胞低浓度皮质酮是通过GR诱导ERS。
Infection is a common complication after severe trauma. there are still no effective therapeutic strategies so far. Therefore, the prevention and treatment of injury-induced organ dysfunction is very important at the early stage of injury. Major trauma results in massive impairment of immunologic reactivity, which has been demonstrated to correlate clinically with increased susceptibility to serious infection. It has been found to elicit neuroendocrine responses immediately after trauma. There is increasing evidence revealing that the neuroendocrine system is important in the regulation of immune function. The key neuroendocrine response to stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, The glucocorticoids (GCs) are the final effectors of the HPA axis. These GCs play an important role in the modulation of the immune system. GCs are regarded widely as being immunosuppressive and are used clinically as antiinflammatory agents. A growing body of literature suggests that, far from being suppressive, endogenous or natural GCs are also known to exert immunostimulatory effects. Previous study showed that GCs can enhance the immune functions of peritoneal macrophages, specially at low concentrations. However, the precise cellular mechanisms underlying the immunostimulatory effects of GCs have not been fully elucidated.
The endoplasmic reticulum (ER) is a critical organelle involved in intracellular calcium regulation and protein folding, which are crucial for cellular homeostasis. Once ER homeostasis is perturbed by various stressors, newly synthesized unfolded proteins accumulate in the ER, resulting in ER stress (ERS). To cope with accumlated unfolded ER proteins, mammalian cells trigger a specific adaptive response called the unfolded protein response (UPR). UPR is crucial both for cell recovery under condition of ERS and for the function and survival of active secretory cells, such as immune cells. Macrophages are ubiquitous in mammalian tissues and play a central role in both innate and acquired immune responses. Recently, emerging evidence indicates that ERS in immune cells has been shown to play an important role in the regulation of the cellular functions, such as antigen presentation, plasma cell differentiation and antibody production, and T cell response to antigen. In addition, there is also increasing evidence indicating a strong link between ERS and immune inflammatory response. ERS-induced transcription factors, such as X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6) have been demonstrated to play an essential role in ERS-induced changes in cellular functions. However, the effects of GCs on macrophage ERS and its relationship with the immunostimulatory effects have yet to be defined.
Based on our previous findings and current researches, the aim of this work was to investigate whether the immunostimulatory effects of GCs mediated by ERS and their potential molecular mechanisms, which includes the following four aspects: (1) To observe the expression changes of ERS-associated molecules GRP78, XBP1 and ATF6 in mice peritoneal macrophages treated with various concentrations of endogenous GCs (corticosterone). In order to further elucidate the relationship between ERS and altered immune functions, we investigated the effects of thapsigargin, an ERS inducer, on immune functions of mice peritoneal macrophages. Furthermore, to investigate the relationship the immunosuppressive effects of GCs between ERS in vitro. (2) We used CRH knockout (CRH-/-) mice, to observe in vivo the effects of the HPA axis activation on ERS and immune functions of immune cells of mice exposed to acute restraint stress. (3) Using lentiviral-mediated RNAi (RNA interference) technology, selectively silenceing of the XBP1 gene in mice, to investigate the role of XBP1 in the immunostimulatory effects of low concentration of corticosterone in vitro. (4) To use the GR antagonists RU486 (mifepristone) to explore the relationship between low concentration of corticosterone-induced ERS and GR. The purpose of this study is to further elucidate the molecular mechanisms of the immunostimulatory effects of GCs, and then provide more evidence for deepening the understanding of the regulation of the neuroendocrine system on the immune function.
The main results are shown as follows:
1. Previous works indicate that low concentrations of GCs exert immunostimulatory effects on macrophages function. In order to test the hypothesis that GCs induces ERS in mice peritoneal macrophages, and to elucidate the role of ERS in low concentrations of GCs-induced immunostimulation. We treated mice peritoneal macrophages with various concentrations of corticosterone, a major type of endogenous GCs in rodents, to observe the GCs-induced ERS. Meanwhile, we further examined the expression of XBP1 and ATF6, two key transcription factors of UPR signaling pathway. In parallel to induction of ERS, low concentrations of corticosterone (10 ng/ml and 50 ng/ml) could also activate the UPR. Splicing of XBP1 mRNA and ATF6 cleavage were observed in mice peritoneal macrophages. In order to further elucidate the relationship between ERS and altered immune functions of macrophages, we investigated the effects of thapsigargin, an ERS inducer, on macrophage function. Similar to the immunostimulatory effects of low concentrations of corticosterone, thapsigarin could enhance macrophages chemotaxis, phagocytosis and TNF-αproduction. However, high concentrations of corticosterone (1000 ng/ml) exert immunosuppressive effects on mouse macrophages (RAW264.7 cells) following stimulation with lipopolysaccharide (LPS), and inhibit LPS-induced ERS of RAW264.7 cells.
2. Corticotropin-releasing hormone (CRH) is the most proximal element of the HPA axis, and it acts as central coordinator for neuroendocrine response to stress. To further examine the effects of HPA axis activation on ERS of immune cells and its relationship with altered immune functions in vivo, we investigated the expression of GRP78, XBP1 and ATF6 and altered immune functions of immune cells of CRH knockout mice exposed to the psychological stress (restraint stress) for 1 h. Our results show that following acute restraint stress, compared to CRH-/- mice, the mRNA and protein expression levels of GRP78 were significantly increaed in immune cells of CRH+/+ or CRH+/- mice. Meanwhile, IRE1/XBP1 and ATF6 signaling pathway were activated. Furthermore, we show here that the immune functions of primary peritoneal macrophages of CRH+/+ or CRH+/- mice was greatly enhanced, compared to those of CRH-/- mice.
3. To explore the role of XBP1 in modulation of macrophage functions by GCs, after construction and screening of lentiviral vector of RNA interference of mouse XBP1 gene, we selectively inactivated the XBP1 gene in mice peritoneal macrophages infected with XBP1-siRNA lentivirus. We found that low concentration of corticosterone (50 ng/ml) did not increase the cellular phagocytosis and TNF-αproduction.
4. The activities of GCs are mostly mediated by the glucocorticoid receptor (GR). Thus, we investigated the possible role of GR in the induction of ER stress in macrophages by low concentration of corticosterone. Our results showed that pretreatment of macrophages with the classical GR antagonist RU486 (mifepristone) could significantly inhibit the increased expression of GRP78 and XBP1 at both mRNA and protein levels induced by low concentration of corticosterone. Furthermore, blocking of the GR by RU486 partly abolished the immunostimulatory effects of low concentration of corticosterone.
Taken together, we concluded that:
1. In parallel to induction of ERS, low concentrations of corticosterone could also activate the UPR. Similar to the immunostimularoty effects of low concentrations of corticosterone, thapsigarin could enhance macrophages chemotaxis, phagocytosis and TNF-αproduction. high concentrations of corticosterone exert immunosuppressive effects related to ERS. Together, these results suggest that the immunostimulatory effects of low concentrations of corticosterone on macrophages might be related to its induction of intracellular ERS.
2. HPA axis activation could induce ERS and enhance immune functions of immune cells, and also highlight a mechanistic association between the moderate activation of the HPA axis elicited immunostimulatory effects and induced ERS of immune cells.
3. XBP1 might play an important role in modulation of the immunostimulatory effects of low concentration of corticosterone.
4. GR was at least partly responsible for the immunostimulatory effects of macrophages induced by low concentration of corticosterone. Furthermore, low concentration of corticosterone induces ERS via GR in macrophages.
引文
1. Smrcka M, Mrlian A, Karlsson-Valik J, et al. The effect of head injury upon the immune system. Bratisl Lek Listy, 2007, 108(3): 144-148.
2. Cobb JP, O'Keefe GE. Injury research in the genomic era. Lancet, 2004, 363(9426): 2076-2083.
3. Klein DG, Fritsch DE, Amin SG. Wound infection following trauma and burn injuries. Crit Care Nurs Clin North Am, 1995, 7(4): 627-642.
4. Baue AE, Durham R, Faist E. Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock, 1998, 10(2): 79-89.
5. Quattrocchi KB, Frank EH, Miller CH, et al. Suppression of cellular immune activity following severe head injury. J Neurotrauma, 1990, 7(2): 77-87.
6. Kohl BA, Deutschman CS. The inflammatory response to surgery and trauma. Curr Opin Crit Care, 2006, 12(4): 325-332.
7. Vanitallie TB. Stress: a risk factor for serious illness. Metabolism, 2002, 51(6 Suppl 1): 40-45.
8. Faist E, Schinkel C, Zimmer S. Update on the mechanisms of immune suppression of injury and immune modulation. World J Surg, 1996, 20(4): 454-459.
9. Faist E, Kim C. Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis. New Horiz, 1998, 6(2 Suppl): S97-102.
10. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol, 2006, 6(4): 318-328.
11. Correa SG, Maccioni M, Rivero VE, et al. Cytokines and the immune-neuroendocrine network: What did we learn from infection and autoimmunity? Cytokine Growth Factor Rev, 2007, 18(1-2): 125-134.
12. Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun, 2007, 21(1): 34-44.
13. Savastano M, Aita M, Barlani F. Psychological, neural, endocrine, and immune studyof stress in tinnitus patients: any correlation between psychometric and biochemical measures? Ann Otol Rhinol Laryngol, 2007, 116(2): 100-106.
14. Elenkov IJ, Wilder RL, Chrousos GP, et al. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev, 2000, 52(4): 595-638.
15. Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun, 2007, 21(4): 384-392.
16. Turrin NP, Rivest S. Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems. Exp Biol Med (Maywood), 2004, 229(10): 996-1006.
17. Lennon VA. Cross-talk between nervous and immune systems in response to injury. Prog Brain Res, 1994, 103: 289-292.
18. Malarkey WB, Mills PJ. Endocrinology: the active partner in PNI research. Brain Behav Immun, 2007, 21(2): 161-168.
19. Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med, 1993, 119(12): 1198-1208.
20. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev, 2000, 21(1): 55-89.
21. Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages. J Surg Res, 2004, 116(2): 253-261.
22. Kohut ML, Martin AE, Senchina DS, et al. Glucocorticoids produced during exercise may be necessary for optimal virus-induced IL-2 and cell proliferation whereas both catecholamines and glucocorticoids may be required for adequate immune defense to viral infection. Brain Behav Immun, 2005, 19(5): 423-435.
23.周建云,蒋建新,杨策,等.皮质酮对大鼠腹腔巨噬细胞功能的影响.第三军医大学学报, 2008, 30(2): 120-123.
24. Lyte M, Nelson SG, Thompson ML. Innate and adaptive immune responses in a socialconflict paradigm. Clin Immunol Immunopathol, 1990, 57(1): 137-147.
25. Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol, 1996, 156(7): 2608-2615.
26. Ruzek MC, Pearce BD, Miller AH, et al. Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J Immunol, 1999, 162(6): 3527-3533.
27. Lim HY, Muller N, Herold MJ, et al. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology, 2007, 122(1): 47-53.
28. Long F, Wang YX, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005, 70(1): 55-61.
29. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
30. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74: 739-789.
31. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell, 1999, 10(11): 3787-3799.
32. Reddy RK, Mao C, Baumeister P, et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem, 2003, 278(23): 20915-20924.
33. Misra UK, Pizzo SV. Up-regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin. J Leukoc Biol, 2005, 78(1): 187-194.
34. Yoshida H. ER stress and diseases. FEBS J, 2007, 274(3): 630-658.
35. Wang Q, Zhang H, Zhao B, et al. IL-1beta caused pancreatic beta-cells apoptosis is mediated in part by endoplasmic reticulum stress via the induction of endoplasmic reticulum Ca(2+) release through the c-Jun N-terminal kinase pathway. Mol Cell Biochem, 2009, 324(1-2): 183-190.
36. Woods J, Lu Q, Ceddia MA, et al. Special feature for the Olympics: effects of exercise on the immune system: exercise-induced modulation of macrophage function. Immunol Cell Biol, 2000, 78(5): 545-553.
37. Ortega E, Garcia JJ, De la Fuente M. Modulation of adherence and chemotaxis of macrophages by norepinephrine. Influence of ageing. Mol Cell Biochem, 2000, 203(1-2): 113-117.
38. Roy B, Rai U. Dual mode of catecholamine action on splenic macrophage phagocytosis in wall lizard, Hemidactylus flaviviridis. Gen Comp Endocrinol, 2004, 136(2): 180-191.
39. Victor VM, Rocha M, De la Fuente M. Regulation of macrophage function by the antioxidant N-acetylcysteine in mouse-oxidative stress by endotoxin. Int Immunopharmacol, 2003, 3(1): 97-106.
40. Shkoda A, Ruiz PA, Daniel H, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology, 2007, 132(1): 190-207.
41. Gargalovic PS, Gharavi NM, Clark MJ, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol, 2006, 26(11): 2490-2496.
42. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum, 2005, 52(6): 1824-1835.
43. Endo M, Oyadomari S, Suga M, et al. The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J Biochem (Tokyo), 2005, 138(4): 501-507.
44. Smith JA, Turner MJ, Delay ML, et al. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. Eur J Immunol, 2008, 38(5): 1194-1203.
45. de Almeida SF, Fleming JV, Azevedo JE, et al. Stimulation of an unfolded protein response impairs MHC class I expression. J Immunol, 2007, 178(6): 3612-3619.
46. Brewer JW, Hendershot LM. Building an antibody factory: a job for the unfoldedprotein response. Nature Immunology, 2005, 6(1): 23-29.
47. Zhang K, Wong HN, Song B, et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest, 2005, 115(2): 268-281.
48. Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol, 2003, 4(4): 321-329.
49. Pino SC, O'Sullivan-Murphy B, Lidstone EA, et al. Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response. Cell Stress Chaperones, 2008, 13(4): 421-434.
50. Yoshimura FK, Luo X. Induction of endoplasmic reticulum stress in thymic lymphocytes by the envelope precursor polyprotein of a murine leukemia virus during the preleukemic period. J Virol, 2007, 81(8): 4374-4377.
51. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
52. Ryoo HD, Steller H. Unfolded protein response in Drosophila - Why another model can make it fly. Cell Cycle, 2007, 6(7): 830-835.
53. Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol, 2000, 20(18): 6755-6767.
54. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol, 2003, 23(21): 7448-7459.
55. Majors AK, Austin RC, de la Motte CA, et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. J Biol Chem, 2003, 278(47): 47223-47231.
56. Toth A, Nickson P, Mandl A, et al. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets, 2007, 7(3): 205-218.
57. Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr OpinCell Biol, 2006, 18(4): 444-452.
58. Alvarez P, Alvarado C, Puerto M, et al. Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals. Nutrition, 2006, 22(9): 913-921.
59. De la Fuente M, Del Rio M, Medina S. Changes with aging in the modulation by neuropeptide Y of murine peritoneal macrophage functions. J Neuroimmunol, 2001, 116(2): 156-167.
60. Sanchez A, Reeser JL, Lau HS, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr, 1973, 26(11): 1180-1184.
61. Falk W, Goodwin RH, Jr., Leonard EJ. A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods, 1980, 33(3): 239-247.
62. Don MJ, Liao JF, Lin LY, et al. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br J Pharmacol, 2007, 151(5): 638-646.
63. Ortega E, Forner MA, Barriga C. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol, 1997, 498( Pt 3): 729-734.
64. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
65. Bechill J, Chen Z, Brewer JW, et al. Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression. J Virol, 2008, 82(9): 4492-4501.
66. Bischof LJ, Kao CY, Los FC, et al. Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo. PLoS Pathog, 2008, 4(10): e1000176.
67. Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell, 2006, 124(3): 587-599.
68. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and deathdecisions. J Clin Invest, 2005, 115(10): 2656-2664.
69. Vitale A, Boston RS. Endoplasmic reticulum quality control and the unfolded protein response: insights from plants. Traffic, 2008, 9(10): 1581-1588.
70. Wheeler MC, Rizzi M, Sasik R, et al. KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity. J Immunol, 2008, 181(1): 256-264.
71. Hung JH, Su IJ, Lei HY, et al. Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem, 2004, 279(45): 46384-46392.
72. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
73. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. J Biol Chem, 2005, 280(40): 33917-33925.
74. Yarnamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha and XBP1. Developmental Cell, 2007, 13(3): 365-376.
75. Wu J, Rutkowski DT, Dubois M, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell, 2007, 13(3): 351-364.
76. Paschen W, Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium, 2005, 38(3-4): 409-415.
77. Goulding NJ. The molecular complexity of glucocorticoid actions in inflammation - a four-ring circus. Curr Opin Pharmacol, 2004, 4(6): 629-636.
78. Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Curr Opin Crit Care, 2005, 11(5): 449-453.
79. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med, 2005, 353(16): 1711-1723.
80. Saklatvala J. Glucocorticoids: do we know how they work? Arthritis Res, 2002, 4(3):146-150.
81. Drouin J, Sun YL, Chamberland M, et al. Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J, 1993, 12(1): 145-156.
82. Meyer T, Gustafsson JA, Carlstedt-Duke J. Glucocorticoid-dependent transcriptional repression of the osteocalcin gene by competitive binding at the TATA box. DNA Cell Biol, 1997, 16(8): 919-927.
83. Li C, Li Y, Liu H, et al. Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter. J Mol Endocrinol, 2008, 40(1): 3-12.
84. Gerritsen ME, Williams AJ, Neish AS, et al. CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A, 1997, 94(7): 2927-2932.
85. Sheppard KA, Phelps KM, Williams AJ, et al. Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1. J Biol Chem, 1998, 273(45): 29291-29294.
86. Lasa M, Abraham SM, Boucheron C, et al. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol, 2002, 22(22): 7802-7811.
87. Hermoso MA, Matsuguchi T, Smoak K, et al. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol Cell Biol, 2004, 24(11): 4743-4756.
88. Kassel O, Sancono A, Kratzschmar J, et al. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J, 2001, 20(24): 7108-7116.
89. Wang X, Nelin LD, Kuhlman JR, et al. The role of MAP kinase phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia. Life Sci, 2008, 83(19-20): 671-680.
90. Hiramatsu N, Kasai A, Hayakawa K, et al. Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: evidence for systemic,transient ER stress during endotoxemia. Nucleic Acids Res, 2006, 34(13): e93.
91. Goodall JC, Ellis L, Yeo GS, et al. Does HLA-B27 influence the monocyte inflammatory response to lipopolysaccharide? Rheumatology (Oxford), 2007, 46(2): 232-237.
92. Grivennikov SI, Tumanov AV, Liepinsh DJ, et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity, 2005, 22(1): 93-104.
93. Yokouchi M, Hiramatsu N, Hayakawa K, et al. Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem, 2008, 283(7): 4252-4260.
94. He S, Yaung J, Kim YH, et al. Endoplasmic reticulum stress induced by oxidative stress in retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol, 2008, 246(5): 677-683.
95. Holtz WA, Turetzky JM, Jong YJ, et al. Oxidative stress-triggered unfolded protein response is upstream of intrinsic cell death evoked by parkinsonian mimetics. J Neurochem, 2006, 99(1): 54-69.
96. Kozlov AV, Duvigneau JC, Miller I, et al. Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. Biochim Biophys Acta, 2009.
97. Gaut JR, Hendershot LM. The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol, 1993, 5(4): 589-595.
98. Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep, 2006, 7(9): 880-885.
99. van Anken E, Braakman I. Endoplasmic reticulum stress and the making of a professional secretory cell. Critical Reviews in Biochemistry and Molecular Biology, 2005, 40(5): 269-283.
100. Gass JN, Jiang HY, Wek RC, et al. The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Mol Immunol, 2008, 45(4): 1035-1043.
101. Tazi KA, Bieche I, Paradis V, et al. In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J Hepatol, 2007,46(6): 1075-1088.
102. Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res, 2005, 569(1-2): 29-63.
103. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab, 2002, 13(9): 373-380.
104. Kapoor A, Dunn E, Kostaki A, et al. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol, 2006, 572(Pt 1): 31-44.
105. Rivier J, Spiess J, Vale W. Characterization of rat hypothalamic corticotropin-releasing factor. Proc Natl Acad Sci U S A, 1983, 80(15): 4851-4855.
106. Venihaki M, Zhao J, Karalis KP. Corticotropin-releasing hormone deficiency results in impaired splenocyte response to lipopolysaccharide. J Neuroimmunol, 2003, 141(1-2): 3-9.
107. Aird F, Clevenger CV, Prystowsky MB, et al. Corticotropin-releasing factor mRNA in rat thymus and spleen. Proc Natl Acad Sci U S A, 1993, 90(15): 7104-7108.
108. Ekman R, Servenius B, Castro MG, et al. Biosynthesis of corticotropin-releasing hormone in human T-lymphocytes. J Neuroimmunol, 1993, 44(1): 7-13.
109. Muglia LJ, Jenkins NA, Gilbert DJ, et al. Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. J Clin Invest, 1994, 93(5): 2066-2072.
110. Dunn AJ, Berridge CW. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Brain Res Rev, 1990, 15(2): 71-100.
111. Venihaki M, Majzoub JA. Animal models of CRH deficiency. Front Neuroendocrinol, 1999, 20(2): 122-145.
112. Muglia L, Jacobson L, Dikkes P, et al. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature, 1995, 373(6513): 427-432.
113. Venihaki M, Carrigan A, Dikkes P, et al. Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency. Proc Natl AcadSci U S A, 2000, 97(13): 7336-7341.
114. Muglia LJ, Bae DS, Brown TT, et al. Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice. Am J Respir Cell Mol Biol, 1999, 20(2): 181-188.
115. Webster EL, Torpy DJ, Elenkov IJ, et al. Corticotropin-releasing hormone and inflammation. Ann N Y Acad Sci, 1998, 840: 21-32.
116. Karalis K, Muglia LJ, Bae D, et al. CRH and the immune system. J Neuroimmunol, 1997, 72(2): 131-136.
117. Vale W, Spiess J, Rivier C, et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 1981, 213(4514): 1394-1397.
118. Jessop DS, Harbuz MS, Lightman SL. CRH in chronic inflammatory stress. Peptides, 2001, 22(5): 803-807.
119. Patel S, Roelke CT, Rademacher DJ, et al. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology, 2004, 145(12): 5431-5438.
120. Rademacher DJ, Meier SE, Shi L, et al. Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology, 2008, 54(1): 108-116.
121. Maddali S, Stapleton PP, Freeman TA, et al. Neuroendocrine responses mediate macrophage function after trauma. Surgery, 2004, 136(5): 1038-1046.
122. Selye H, Fortier C. Adaptive reaction to stress. Psychosom Med, 1950, 12(3): 149-157.
123. Selye H. Endocrine reactions during stress. Curr Res Anesth Analg, 1956, 35(3): 182-193.
124. Selye H. Implications of stress concept. N Y State J Med, 1975, 75(12): 2139-2145.
125. DeBold CR, Sheldon WR, DeCherney GS, et al. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest, 1984, 73(2): 533-538.
126. Van de Kar LD, Blair ML. Forebrain pathways mediating stress-induced hormonesecretion. Front Neuroendocrinol, 1999, 20(1): 1-48.
127. Dhabhar FS. Stress-induced enhancement of cell-mediated immunity. Ann N Y Acad Sci, 1998, 840: 359-372.
128. Zhou D, Kusnecov AW, Shurin MR, et al. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology, 1993, 133(6): 2523-2530.
129. Marin MT, Cruz FC, Planeta CS. Chronic restraint or variable stresses differently affect the behavior, corticosterone secretion and body weight in rats. Physiol Behav, 2007, 90(1): 29-35.
130. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95(10): 957-970.
131. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ, 2006, 13(3): 363-373.
132. Muglia LJ, Jacobson L, Weninger SC, et al. The physiology of corticotropin-releasing hormone deficiency in mice. Peptides, 2001, 22(5): 725-731.
133. Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol, 2003, 24(8): 444-448.
134. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol, 2005, 5(3): 243-251.
135. Kusnecov AW, Rabin BS. Stressor-induced alterations of immune function: mechanisms and issues. Int Arch Allergy Immunol, 1994, 105(2): 107-121.
136. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull, 2004, 130(4): 601-630.
137. Pruett SB. Quantitative aspects of stress-induced immunomodulation. Int Immunopharmacol, 2001, 1(3): 507-520.
138. Hermann G, Beck FM, Sheridan JF. Stress-induced glucocorticoid response modulates mononuclear cell trafficking during an experimental influenza viral infection. J Neuroimmunol, 1995, 56(2): 179-186.
139. Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking. Ann N Y Acad Sci, 2000, 917:876-893.
140. Dhabhar FS. Stress-induced augmentation of immune function--the role of stress hormones, leukocyte trafficking, and cytokines. Brain Behav Immun, 2002, 16(6): 785-798.
141. Dhabhar FS. Stress, leukocyte trafficking, and the augmentation of skin immune function. Ann N Y Acad Sci, 2003, 992: 205-217.
142. Chancellor-Freeland C, Zhu GF, Kage R, et al. Substance P and stress-induced changes in macrophages. Ann N Y Acad Sci, 1995, 771: 472-484.
143. Deak T, Meriwether JL, Fleshner M, et al. Evidence that brief stress may induce the acute phase response in rats. Am J Physiol, 1997, 273(6 Pt 2): R1998-2004.
144. Fleshner M, Nguyen KT, Cotter CS, et al. Acute stressor exposure both suppresses acquired immunity and potentiates innate immunity. Am J Physiol, 1998, 275(3 Pt 2): R870-878.
145. Campisi J, Fleshner M. Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J Appl Physiol, 2003, 94(1): 43-52.
146. Saint-Mezard P, Chavagnac C, Bosset S, et al. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol, 2003, 171(8): 4073-4080.
147. Harmsen AG, Turney TH. Inhibition of in vivo neutrophil accumulation by stress. Possible role of neutrophil adherence. Inflammation, 1985, 9(1): 9-20.
148. Shurin MR, Kusnecov A, Hamill E, et al. Stress-induced alteration of polymorphonuclear leukocyte function in rats. Brain Behav Immun, 1994, 8(2): 163-169.
149. Jain S, Stevenson JR. Enhancement by restraint stress of natural killer cell activity and splenocyte responsiveness to concanavalin A in Fischer 344 rats. Immunol Invest, 1991, 20(4): 365-376.
150. LeMay LG, Vander AJ, Kluger MJ. The effects of psychological stress on plasma interleukin-6 activity in rats. Physiol Behav, 1990, 47(5): 957-961.
151. Maes M, Hendriks D, Van Gastel A, et al. Effects of psychological stress on serum immunoglobulin, complement and acute phase protein concentrations in normal volunteers. Psychoneuroendocrinology, 1997, 22(6): 397-409.
152. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 2002, 415(6867): 92-96.
153. Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 2001, 107(7): 881-891.
154. Liou HC, Boothby MR, Finn PW, et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science, 1990, 247(4950): 1581-1584.
155. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 2001, 411(6836): 494-498.
156. Kirchhoff F. Silencing HIV-1 In Vivo. Cell, 2008, 134(4): 566-568.
157. Grimm D, Kay MA. Therapeutic application of RNAi: is mRNA targeting finally ready for prime time? J Clin Invest, 2007, 117(12): 3633-3641.
158. Morris KV, Rossi JJ. Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther, 2006, 13(6): 553-558.
159. Huang HY, Lee CC, Chiang BL. Small interfering RNA against interleukin-5 decreases airway eosinophilia and hyper-responsiveness. Gene Ther, 2008, 15(9): 660-667.
160. Kim YJ, Ahn J, Jeung SY, et al. Recombinant lentivirus-delivered short hairpin RNAs targeted to conserved coxsackievirus sequences protect against viral myocarditis and improve survival rate in an animal model. Virus Genes, 2008, 36(1): 141-146.
161. Lee CC, Huang HY, Chiang BL. Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness. Mol Ther, 2008, 16(1): 60-65.
162. Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha and XBP1. Dev Cell, 2007, 13(3): 365-376.
163. Lin JH, Li H, Yasumura D, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science, 2007, 318(5852): 944-949.
164. Lin JH, Li H, Zhang Y, et al. Divergent effects of PERK and IRE1 signaling on cellviability. PLoS ONE, 2009, 4(1): e4170.
165. van Huizen R, Martindale JL, Gorospe M, et al. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem, 2003, 278(18): 15558-15564.
166. Sriburi R, Jackowski S, Mori K, et al. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol, 2004, 167(1): 35-41.
167. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
168. Yoshida H. Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal, 2007, 9(12): 2323-2333.
169. Nishikawa S, Brodsky JL, Nakatsukasa K. Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem, 2005, 137(5): 551-555.
170. Ogawa S, Lozach J, Benner C, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell, 2005, 122(5): 707-721.
171. Wright AP, Zilliacus J, McEwan IJ, et al. Structure and function of the glucocorticoid receptor. J Steroid Biochem Mol Biol, 1993, 47(1-6): 11-19.
172. Butts CL, Sternberg EM. Neuroendocrine factors alter host defense by modulating immune function. Cell Immunol, 2008, 252(1-2): 7-15.
173. Elenkov IJ, Chrousos GP. Stress system--organization, physiology and immunoregulation. Neuroimmunomodulation, 2006, 13(5-6): 257-267.
174. Bowers SL, Bilbo SD, Dhabhar FS, et al. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun, 2008, 22(1): 105-113.
175. Rinehart JJ, Balcerzak SP, Sagone AL, et al. Effects of corticosteroids on human monocyte function. J Clin Invest, 1974, 54(6): 1337-1343.
176. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol, 2006, 102(1-5): 11-21.
177. Song IH, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments. Mol Cell Endocrinol, 2006, 246(1-2): 142-146.
178. Haller J, Mikics E, Makara GB. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front Neuroendocrinol, 2008, 29(2): 273-291.
179. Joels M, De Kloet ER. Coordinative mineralocorticoid and glucocorticoid receptor-mediated control of responses to serotonin in rat hippocampus. Neuroendocrinology, 1992, 55(3): 344-350.
180. Liu W, Wang J, Sauter NK, et al. Steroid receptor heterodimerization demonstrated in vitro and in vivo. Proc Natl Acad Sci U S A, 1995, 92(26): 12480-12484.
181. Trapp T, Holsboer F. Heterodimerization between mineralocorticoid and glucocorticoid receptors increases the functional diversity of corticosteroid action. Trends Pharmacol Sci, 1996, 17(4): 145-149.
182. Moguilewsky M, Philibert D. RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation. J Steroid Biochem, 1984, 20(1): 271-276.
183. Honer C, Nam K, Fink C, et al. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Mol Pharmacol, 2003, 63(5): 1012-1020.
1. Kitamura M. Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008, 12(5): 317-325.
2. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
3. Gaut JR, Hendershot LM. The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol, 1993, 5(4): 589-595.
4. Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep, 2006, 7(9): 880-885.
5. Lee AS. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci, 2001, 26(8): 504-510.
6. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
7. Yoshida H. ER stress and diseases. FEBS J, 2007, 274(3): 630-658.
8. Fewell SW, Travers KJ, Weissman JS, et al. The action of molecular chaperones in the early secretory pathway. Annu Rev Genet, 2001, 35: 149-191.
9. Ellgaard L, Molinari M, Helenius A. Setting the standards: quality control in the secretory pathway. Science, 1999, 286(5446): 1882-1888.
10. Cid VJ, Duran A, del Rey F, et al. Molecular basis of cell integrity and morphogenesis in Saccharomyces cerevisiae. Microbiol Rev, 1995, 59(3): 345-386.
11. Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell, 2000, 101(5): 451-454.
12. Ma Y, Hendershot LM. The unfolding tale of the unfolded protein response. Cell, 2001, 107(7): 827-830.
13. Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res, 2005, 569(1-2): 29-63.
14. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74:739-789.
15. Pahl HL. Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev, 1999, 79(3): 683-701.
16. Pakula TM, Laxell M, Huuskonen A, et al. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J Biol Chem, 2003, 278(45): 45011-45020.
17. Martinez IM, Chrispeels MJ. Genomic analysis of the unfolded protein response in Arabidopsis shows its connection to important cellular processes. Plant Cell, 2003, 15(2): 561-576.
18. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by anendoplasmic-reticulum-resident kinase. Nature, 1999, 397(6716): 271-274.
19. Casagrande R, Stern P, Diehn M, et al. Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol Cell, 2000, 5(4): 729-735.
20. Friedlander R, Jarosch E, Urban J, et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol, 2000, 2(7): 379-384.
21. Travers KJ, Patil CK, Wodicka L, et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell, 2000, 101(3): 249-258.
22. Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol, 2004, 14(1): 20-28.
23. Ma Y, Hendershot LM. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell Stress Chaperones, 2002, 7(2): 222-229.
24. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell, 1999, 10(11): 3787-3799.
25. Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 2001, 107(7): 881-891.
26. Lee K, Tirasophon W, Shen X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev, 2002, 16(4): 452-466.
27. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 2002, 415(6867): 92-96.
28. Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol, 2000, 2(6): 326-332.
29. Shen J, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell, 2002, 3(1): 99-111.
30. Kimata Y, Kimata YI, Shimizu Y, et al. Genetic evidence for a role of BiP/Kar2 thatregulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell, 2003, 14(6): 2559-2569.
31. Credle JJ, Finer-Moore JS, Papa FR, et al. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A, 2005, 102(52): 18773-18784.
32. Kimata Y, Ishiwata-Kimata Y, Ito T, et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J Cell Biol, 2007, 179(1): 75-86.
33. Wang XZ, Harding HP, Zhang Y, et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J, 1998, 17(19): 5708-5717.
34. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
35. Tirasophon W, Lee K, Callaghan B, et al. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev, 2000, 14(21): 2725-2736.
36. Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J, 1996, 15(12): 3028-3039.
37. Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev, 2002, 16(11): 1345-1355.
38. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science, 2000, 287(5453): 664-666.
39. Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol, 2006, 26(24): 9220-9231.
40. Maiuri MC, Zalckvar E, Kimchi A, et al. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 2007, 8(9): 741-752.
41. Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem, 2001,276(17): 13935-13940.
42. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
43. Clevers H. Inflammatory bowel disease, stress, and the endoplasmic reticulum. N Engl J Med, 2009, 360(7): 726-727.
44. Kokame K, Kato H, Miyata T. Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response. J Biol Chem, 2001, 276(12): 9199-9205.
45. Lee AH, Iwakoshi NN, Anderson KC, et al. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A, 2003, 100(17): 9946-9951.
46. Tirosh B, Iwakoshi NN, Glimcher LH, et al. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J Biol Chem, 2006, 281(9): 5852-5860.
47. Yoshida H, Oku M, Suzuki M, et al. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. Journal of Cell Biology, 2006, 172(4): 565-575.
48. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol, 2003, 23(21): 7448-7459.
49. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 2004, 21(1): 81-93.
50. Shen Y, Hendershot LM. Identification of ERdj3 and OBF-1/BOB-1/OCA-B as direct targets of XBP-1 during plasma cell differentiation. J Immunol, 2007, 179(5): 2969-2978.
51. Lee AH, Scapa EF, Cohen DE, et al. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science, 2008, 320(5882): 1492-1496.
52. Sriburi R, Jackowski S, Mori K, et al. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol, 2004, 167(1): 35-41.
53. Liou HC, Boothby MR, Finn PW, et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science, 1990, 247(4950): 1581-1584.
54. Clauss IM, Gravallese EM, Darling JM, et al. In situ hybridization studies suggest a role for the basic region-leucine zipper protein hXBP-1 in exocrine gland and skeletal development during mouse embryogenesis. Dev Dyn, 1993, 197(2): 146-156.
55. Reimold AM, Etkin A, Clauss I, et al. An essential role in liver development for transcription factor XBP-1. Genes Dev, 2000, 14(2): 152-157.
56. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
57. Hetz C, Bernasconi P, Fisher J, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science, 2006, 312(5773): 572-576.
58. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol, 2008, 8(9): 663-674.
59. Gu F, Nguyen DT, Stuible M, et al. Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. J Biol Chem, 2004, 279(48): 49689-49693.
60. Hetz C, Glimcher L. The daily job of night killers: alternative roles of the BCL-2 family in organelle physiology. Trends in Cell Biology, 2008, 18(1): 38-44.
61. Shi Y, Vattem KM, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol, 1998, 18(12): 7499-7509.
62. Brewer JW, Diehl JA. PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A, 2000, 97(23): 12625-12630.
63. Harding HP, Zhang Y, Bertolotti A, et al. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell, 2000, 5(5): 897-904.
64. Clemens MJ. Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis. Prog Mol Subcell Biol, 2001, 27: 57-89.
65. Hamanaka RB, Bennett BS, Cullinan SB, et al. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded proteinresponse pathway. Mol Biol Cell, 2005, 16(12): 5493-5501.
66. Novoa I, Zeng H, Harding HP, et al. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol, 2001, 153(5): 1011-1022.
67. Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev, 2004, 18(24): 3066-3077.
68. Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell, 2000, 6(6): 1355-1364.
69. Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem, 2002, 277(15): 13045-13052.
70. van Huizen R, Martindale JL, Gorospe M, et al. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem, 2003, 278(18): 15558-15564.
71. Bailey D, O'Hare P. Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid Redox Signal, 2007, 9(12): 2305-2321.
72. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 1997, 89(3): 331-340.
73. Haze K, Okada T, Yoshida H, et al. Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem J, 2001, 355(Pt 1): 19-28.
74. Thuerauf DJ, Morrison L, Glembotski CC. Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem, 2004, 279(20): 21078-21084.
75. Adachi Y, Yamamoto K, Okada T, et al. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct, 2008, 33(1): 75-89.
76. Yarnamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha andXBP1. Dev Cell, 2007, 13(3): 365-376.
77. Wu J, Rutkowski DT, Dubois M, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell, 2007, 13(3): 351-364.
78. Wang Y, Shen J, Arenzana N, et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem, 2000, 275(35): 27013-27020.
79. Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem, 1998, 273(50): 33741-33749.
80. Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol, 2000, 20(18): 6755-6767.
81. Roy B, Lee AS. The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res, 1999, 27(6): 1437-1443.
82. Gass JN, Gunn KE, Sriburi R, et al. Stressed-out B cells? Plasma-cell differentiation and the unfolded protein response. Trends in Immunology, 2004, 25(1): 17-24.
83. Yan W, Frank CL, Korth MJ, et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci U S A, 2002, 99(25): 15920-15925.
84. Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev, 1998, 12(7): 982-995.
85. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95(10): 957-970.
86. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest, 2005, 115(10): 2656-2664.
87. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ, 2006, 13(3): 363-373.
1. Kitamura M. Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008, 12(5): 317-325.
2. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
3. Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature, 2001, 412(6844): 300-307.
4. Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol, 2003, 4(4): 321-329.
5. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 2004, 21(1): 81-93.
6. Gass JN, Gifford NM, Brewer JW. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J Biol Chem, 2002, 277(50): 49047-49054.
7. Tirosh B, Iwakoshi NN, Glimcher LH, et al. XBP-1 specifically promotes IgMsynthesis and secretion, but is dispensable for degradation of glycoproteins in primary B cells. J Exp Med, 2005, 202(4): 505-516.
8. Skalet AH, Isler JA, King LB, et al. Rapid B cell receptor-induced unfolded protein response in nonsecretory B cells correlates with pro- versus antiapoptotic cell fate. J Biol Chem, 2005, 280(48): 39762-39771.
9. Rush JS, Sweitzer T, Kent C, et al. Biogenesis of the endoplasmic reticulum in activated B lymphocytes: temporal relationships between the induction of protein N-glycosylation activity and the biosynthesis of membrane protein and phospholipid. Arch Biochem Biophys, 1991, 284(1): 63-70.
10. Wiest DL, Burkhardt JK, Hester S, et al. Membrane biogenesis during B cell differentiation: most endoplasmic reticulum proteins are expressed coordinately. J Cell Biol, 1990, 110(5): 1501-1511.
11. Zhang K, Wong HN, Song B, et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest, 2005, 115(2): 268-281.
12. Gass JN, Jiang HY, Wek RC, et al. The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Mol Immunol, 2008, 45(4): 1035-1043.
13. Iwakoshi NN, Pypaert M, Glimcher LH. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J Exp Med, 2007, 204(10): 2267-2275.
14. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol, 2008, 8(9): 663-674.
15. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature, 2008, 454(7203): 455-462.
16. Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci, 2000, 25(10): 502-508.
17. Tu BP, Weissman JS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol, 2004, 164(3): 341-346.
18. Tu BP, Weissman JS. The FAD- and O(2)-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum. Mol Cell, 2002, 10(5):983-994.
19. Cullinan SB, Zhang D, Hannink M, et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol, 2003, 23(20): 7198-7209.
20. Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell, 2003, 11(3): 619-633.
21. Mathers J, Fraser JA, McMahon M, et al. Antioxidant and cytoprotective responses to redox stress. Biochem Soc Symp, 2004, 71: 157-176.
22. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev, 2006, 38(4): 769-789.
23. Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem, 2004, 279(19): 20108-20117.
24. Sekine Y, Takeda K, Ichijo H. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med, 2006, 6(1): 87-97.
25. Hu P, Han Z, Couvillon AD, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol, 2006, 26(8): 3071-3084.
26. Kaneko M, Niinuma Y, Nomura Y. Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull, 2003, 26(7): 931-935.
27. Deng J, Lu PD, Zhang Y, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol, 2004, 24(23): 10161-10168.
28. Jiang HY, Wek SA, McGrath BC, et al. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol, 2003, 23(16): 5651-5663.
29. Rius J, Guma M, Schachtrup C, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature, 2008, 453(7196): 807-811.
30. Pahl HL, Baeuerle PA. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B. J Virol, 1995, 69(3): 1480-1484.
31. Meyer M, Caselmann WH, Schluter V, et al. Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. EMBO J, 1992, 11(8): 2991-3001.
32. Pahl HL, Baeuerle PA. Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett, 1996, 392(2): 129-136.
33. Deniaud A, Sharaf el dein O, Maillier E, et al. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene, 2008, 27(3): 285-299.
34. Wu S, Tan M, Hu Y, et al. Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J Biol Chem, 2004, 279(33): 34898-34902.
35. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science, 2000, 287(5453): 664-666.
36. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell, 2000, 103(2): 239-252.
37. Hayakawa K, Hiramatsu N, Okamura M, et al. Blunted activation of NF-kappaB and NF-kappaB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response. Biochem Biophys Res Commun, 2008, 365(1): 47-53.
38. Takano Y, Hiramatsu N, Okamura M, et al. Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response. Biochem Biophys Res Commun, 2007, 360(2): 470-475.
39. Endo S, Hiramatsu N, Hayakawa K, et al. Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. Molecular Pharmacology, 2007, 72(5): 1337-1348.
40. Hayakawa K, Hiramatsu N, Okamura M, et al. Acquisition of anergy to proinflammatory cytokines in nonimmune cells through endoplasmic reticulum stress response: a mechanism for subsidence of inflammation. J Immunol, 2009, 182(2):1182-1191.
41. Devin A, Lin Y, Yamaoka S, et al. The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol, 2001, 21(12): 3986-3994.
42. Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell, 2000, 6(6): 1355-1364.
43. Brown MS, Ye J, Rawson RB, et al. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell, 2000, 100(4): 391-398.
44. Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell, 2006, 124(3): 587-599.
45. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol, 2003, 4(7): 517-529.
46. Gorlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal, 2006, 8(9-10): 1391-1418.
47. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxidants & Redox Signaling, 2007, 9(12): 2277-2293.
48. Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science, 1992, 258(5090): 1898-1902.
49. Uehara T, Nakamura T, Yao D, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature, 2006, 441(7092): 513-517.
50. Xu W, Liu L, Charles IG, et al. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol, 2004, 6(11): 1129-1134.
51. Xu KY, Huso DL, Dawson TM, et al. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci U S A, 1999, 96(2): 657-662.
52. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. J Biol Chem, 2005,280(40): 33917-33925.
53. Lin W, Harding HP, Ron D, et al. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol, 2005, 169(4): 603-612.
54. Feng B, Yao PM, Li Y, et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol, 2003, 5(9): 781-792.
55. Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest, 2002, 110(6): 851-860.
56. Kharroubi I, Ladriere L, Cardozo AK, et al. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology, 2004, 145(11): 5087-5096.
57. Zhou J, Werstuck GH, Lhotak S, et al. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation, 2004, 110(2): 207-213.
58. Yamamuro A, Yoshioka Y, Ogita K, et al. Involvement of endoplasmic reticulum stress on the cell death induced by 6-hydroxydopamine in human neuroblastoma SH-SY5Y cells. Neurochem Res, 2006, 31(5): 657-664.
59. Hotamisligil GS. Inflammation and metabolic disorders. Nature, 2006, 444(7121): 860-867.
60. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
61. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 2004, 306(5695): 457-461.
62. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science, 2006, 313(5790): 1137-1140.
63. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature, 2002, 420(6913): 333-336.
64. Aguirre V, Werner ED, Giraud J, et al. Phosphorylation of Ser307 in insulin receptorsubstrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem, 2002, 277(2): 1531-1537.
65. Tuncman G, Hirosumi J, Solinas G, et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci U S A, 2006, 103(28): 10741-10746.
66. Williams KJ, Tabas I. Atherosclerosis and inflammation. Science, 2002, 297(5581): 521-522.
67. Li Y, Schwabe RF, DeVries-Seimon T, et al. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem, 2005, 280(23): 21763-21772.
68. Gargalovic PS, Gharavi NM, Clark MJ, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol, 2006, 26(11): 2490-2496.
69. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol, 2007, 208(1): 1-25.
70. Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell Death Differ, 2006, 13(3): 385-392.
71. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science, 2001, 292(5521): 1552-1555.
72. Nishitoh H, Kadowaki H, Nagai A, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev, 2008, 22(11): 1451-1464.
73. Wang HQ, Takahashi R. Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson's disease. Antioxid Redox Signal, 2007, 9(5): 553-561.
74. Silva RM, Ries V, Oo TF, et al. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem, 2005, 95(4): 974-986.
75. Hetz C, Lee AH, Gonzalez-Romero D, et al. Unfolded protein response transcriptionfactor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci U S A, 2008, 105(2): 757-762.
76. Paschen W, Aufenberg C, Hotop S, et al. Transient cerebral ischemia activates processing of xbp1 messenger RNA indicative of endoplasmic reticulum stress. J Cereb Blood Flow Metab, 2003, 23(4): 449-461.
77. DeLegge MH, Smoke A. Neurodegeneration and inflammation. Nutr Clin Pract, 2008, 23(1): 35-41.
78. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med, 2006, 354(9): 942-955.
79. Lin W, Kemper A, Dupree JL, et al. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain, 2006, 129(Pt 5): 1306-1318.
80. Lin W, Bailey SL, Ho H, et al. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest, 2007, 117(2): 448-456.
81. Lees JR, Cross AH. A little stress is good: IFN-gamma, demyelination, and multiple sclerosis. J Clin Invest, 2007, 117(2): 297-299.
82. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008, 134(5): 743-756.
83. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
84. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
85. Clevers H. Inflammatory bowel disease, stress, and the endoplasmic reticulum. N Engl J Med, 2009, 360(7): 726-727.
86. Kubota K, Niinuma Y, Kaneko M, et al. Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem, 2006, 97(5): 1259-1268.
87. Qi X, Hosoi T, Okuma Y, et al. Sodium 4-phenylbutyrate protects against cerebralischemic injury. Mol Pharmacol, 2004, 66(4): 899-908.
88. Liu L, Done SC, Khoshnoodi J, et al. Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. Hum Mol Genet, 2001, 10(23): 2637-2644.
89. Sawada N, Yao J, Hiramatsu N, et al. Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder. Lab Invest, 2008, 88(5): 553-563.
90. Takizawa S, Izuhara Y, Kitao Y, et al. A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia. Brain Res, 2007, 1183: 124-137.
91. Izuhara Y, Nangaku M, Takizawa S, et al. A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models. Nephrol Dial Transplant, 2008, 23(2): 497-509.
92. Tabata Y, Takano K, Ito T, et al. Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation. Am J Physiol Cell Physiol, 2007, 293(1): C411-418.
1. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol, 2006, 6(4): 318-328.
2. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev, 2000, 21(1): 55-89.
3. Lim HY, Muller N, Herold MJ, et al. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology, 2007, 122(1): 47-53.
4. Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages. J Surg Res, 2004, 116(2): 253-261.
5. Long F, Wang YX, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005, 70(1): 55-61.
6. Hoffmann JA, Kafatos FC, Janeway CA, et al. Phylogenetic perspectives in innate immunity. Science, 1999, 284(5418): 1313-1318.
7. Doherty DE, Haslett C, Tonnesen MG, et al. Human monocyte adherence: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endothelium. J Immunol, 1987, 138(6): 1762-1771.
8. Baggiolini M. Chemokines in pathology and medicine. J Intern Med, 2001, 250(2): 91-104.
9. Falk W, Goodwin RH, Jr., Leonard EJ. A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods, 1980, 33(3): 239-247.
10. Don MJ, Liao JF, Lin LY, et al. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br J Pharmacol, 2007, 151(5): 638-646.
11. Lim LH, Flower RJ, Perretti M, et al. Glucocorticoid receptor activation reduces CD11b and CD49d levels on murine eosinophils: characterization and functional relevance. Am J Respir Cell Mol Biol, 2000, 22(6): 693-701.
12. Groyer A, Schweizer-Groyer G, Cadepond F, et al. Antiglucocorticosteroid effects suggest why steroid hormone is required for receptors to bind DNA in vivo but not in vitro. Nature, 1987, 328(6131): 624-626.
13. Butts CL, Sternberg EM. Neuroendocrine factors alter host defense by modulating immune function. Cell Immunol, 2008, 252(1-2): 7-15.
14. Elenkov IJ, Chrousos GP. Stress system--organization, physiology and immunoregulation. Neuroimmunomodulation, 2006, 13(5-6): 257-267.
15. Bowers SL, Bilbo SD, Dhabhar FS, et al. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun, 2008, 22(1): 105-113.
16. Rinehart JJ, Balcerzak SP, Sagone AL, et al. Effects of corticosteroids on human monocyte function. J Clin Invest, 1974, 54(6): 1337-1343.
17. Ortega E, Forner MA, Barriga C. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol, 1997, 498( Pt ): 729-734.
18. Baggiolini M, Loetscher P. Chemokines in inflammation and immunity. Immunol Today, 2000, 21(9): 418-420.
19. Taub DD, Oppenheim JJ. Chemokines, inflammation and the immune system. TherImmunol, 1994, 1(4): 229-246.
20. Woods J, Lu Q, Ceddia MA, et al. Special feature for the Olympics: effects of exercise on the immune system: exercise-induced modulation of macrophage function. Immunol Cell Biol, 2000, 78(5): 545-553.
21. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol, 2002, 20: 125-163.
22. Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of stress hormones on skin immune function. Proc Natl Acad Sci U S A, 1999, 96(3): 1059-1064.
23. Lyte M, Nelson SG, Thompson ML. Innate and adaptive immune responses in a social conflict paradigm. Clin Immunol Immunopathol, 1990, 57(1): 137-147.
24. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol, 2006, 102(1-5): 11-21.
25. Song IH, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments. Mol Cell Endocrinol, 2006, 246(1-2): 142-146.
26. Joels M, De Kloet ER. Coordinative mineralocorticoid and glucocorticoid receptor-mediated control of responses to serotonin in rat hippocampus. Neuroendocrinology, 1992, 55(3): 344-350.
27. Liu W, Wang J, Sauter NK, et al. Steroid receptor heterodimerization demonstrated in vitro and in vivo. Proc Natl Acad Sci U S A, 1995, 92(26): 12480-12484.
28. Trapp T, Holsboer F. Heterodimerization between mineralocorticoid and glucocorticoid receptors increases the functional diversity of corticosteroid action. Trends Pharmacol Sci, 1996, 17(4): 145-149.
29. Moguilewsky M, Philibert D. RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation. J Steroid Biochem, 1984, 20(1): 271-276.
30. Honer C, Nam K, Fink C, et al. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Mol Pharmacol, 2003, 63(5): 1012-1020.
2. Cobb JP, O'Keefe GE. Injury research in the genomic era. Lancet, 2004, 363(9426): 2076-2083.
3. Klein DG, Fritsch DE, Amin SG. Wound infection following trauma and burn injuries. Crit Care Nurs Clin North Am, 1995, 7(4): 627-642.
4. Baue AE, Durham R, Faist E. Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock, 1998, 10(2): 79-89.
5. Quattrocchi KB, Frank EH, Miller CH, et al. Suppression of cellular immune activity following severe head injury. J Neurotrauma, 1990, 7(2): 77-87.
6. Kohl BA, Deutschman CS. The inflammatory response to surgery and trauma. Curr Opin Crit Care, 2006, 12(4): 325-332.
7. Vanitallie TB. Stress: a risk factor for serious illness. Metabolism, 2002, 51(6 Suppl 1): 40-45.
8. Faist E, Schinkel C, Zimmer S. Update on the mechanisms of immune suppression of injury and immune modulation. World J Surg, 1996, 20(4): 454-459.
9. Faist E, Kim C. Therapeutic immunomodulatory approaches for the control of systemic inflammatory response syndrome and the prevention of sepsis. New Horiz, 1998, 6(2 Suppl): S97-102.
10. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol, 2006, 6(4): 318-328.
11. Correa SG, Maccioni M, Rivero VE, et al. Cytokines and the immune-neuroendocrine network: What did we learn from infection and autoimmunity? Cytokine Growth Factor Rev, 2007, 18(1-2): 125-134.
12. Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: a personal view. Brain Behav Immun, 2007, 21(1): 34-44.
13. Savastano M, Aita M, Barlani F. Psychological, neural, endocrine, and immune studyof stress in tinnitus patients: any correlation between psychometric and biochemical measures? Ann Otol Rhinol Laryngol, 2007, 116(2): 100-106.
14. Elenkov IJ, Wilder RL, Chrousos GP, et al. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev, 2000, 52(4): 595-638.
15. Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun, 2007, 21(4): 384-392.
16. Turrin NP, Rivest S. Unraveling the molecular details involved in the intimate link between the immune and neuroendocrine systems. Exp Biol Med (Maywood), 2004, 229(10): 996-1006.
17. Lennon VA. Cross-talk between nervous and immune systems in response to injury. Prog Brain Res, 1994, 103: 289-292.
18. Malarkey WB, Mills PJ. Endocrinology: the active partner in PNI research. Brain Behav Immun, 2007, 21(2): 161-168.
19. Boumpas DT, Chrousos GP, Wilder RL, et al. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med, 1993, 119(12): 1198-1208.
20. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev, 2000, 21(1): 55-89.
21. Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages. J Surg Res, 2004, 116(2): 253-261.
22. Kohut ML, Martin AE, Senchina DS, et al. Glucocorticoids produced during exercise may be necessary for optimal virus-induced IL-2 and cell proliferation whereas both catecholamines and glucocorticoids may be required for adequate immune defense to viral infection. Brain Behav Immun, 2005, 19(5): 423-435.
23.周建云,蒋建新,杨策,等.皮质酮对大鼠腹腔巨噬细胞功能的影响.第三军医大学学报, 2008, 30(2): 120-123.
24. Lyte M, Nelson SG, Thompson ML. Innate and adaptive immune responses in a socialconflict paradigm. Clin Immunol Immunopathol, 1990, 57(1): 137-147.
25. Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol, 1996, 156(7): 2608-2615.
26. Ruzek MC, Pearce BD, Miller AH, et al. Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J Immunol, 1999, 162(6): 3527-3533.
27. Lim HY, Muller N, Herold MJ, et al. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology, 2007, 122(1): 47-53.
28. Long F, Wang YX, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005, 70(1): 55-61.
29. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
30. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74: 739-789.
31. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell, 1999, 10(11): 3787-3799.
32. Reddy RK, Mao C, Baumeister P, et al. Endoplasmic reticulum chaperone protein GRP78 protects cells from apoptosis induced by topoisomerase inhibitors: role of ATP binding site in suppression of caspase-7 activation. J Biol Chem, 2003, 278(23): 20915-20924.
33. Misra UK, Pizzo SV. Up-regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin. J Leukoc Biol, 2005, 78(1): 187-194.
34. Yoshida H. ER stress and diseases. FEBS J, 2007, 274(3): 630-658.
35. Wang Q, Zhang H, Zhao B, et al. IL-1beta caused pancreatic beta-cells apoptosis is mediated in part by endoplasmic reticulum stress via the induction of endoplasmic reticulum Ca(2+) release through the c-Jun N-terminal kinase pathway. Mol Cell Biochem, 2009, 324(1-2): 183-190.
36. Woods J, Lu Q, Ceddia MA, et al. Special feature for the Olympics: effects of exercise on the immune system: exercise-induced modulation of macrophage function. Immunol Cell Biol, 2000, 78(5): 545-553.
37. Ortega E, Garcia JJ, De la Fuente M. Modulation of adherence and chemotaxis of macrophages by norepinephrine. Influence of ageing. Mol Cell Biochem, 2000, 203(1-2): 113-117.
38. Roy B, Rai U. Dual mode of catecholamine action on splenic macrophage phagocytosis in wall lizard, Hemidactylus flaviviridis. Gen Comp Endocrinol, 2004, 136(2): 180-191.
39. Victor VM, Rocha M, De la Fuente M. Regulation of macrophage function by the antioxidant N-acetylcysteine in mouse-oxidative stress by endotoxin. Int Immunopharmacol, 2003, 3(1): 97-106.
40. Shkoda A, Ruiz PA, Daniel H, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology, 2007, 132(1): 190-207.
41. Gargalovic PS, Gharavi NM, Clark MJ, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol, 2006, 26(11): 2490-2496.
42. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum, 2005, 52(6): 1824-1835.
43. Endo M, Oyadomari S, Suga M, et al. The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. J Biochem (Tokyo), 2005, 138(4): 501-507.
44. Smith JA, Turner MJ, Delay ML, et al. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. Eur J Immunol, 2008, 38(5): 1194-1203.
45. de Almeida SF, Fleming JV, Azevedo JE, et al. Stimulation of an unfolded protein response impairs MHC class I expression. J Immunol, 2007, 178(6): 3612-3619.
46. Brewer JW, Hendershot LM. Building an antibody factory: a job for the unfoldedprotein response. Nature Immunology, 2005, 6(1): 23-29.
47. Zhang K, Wong HN, Song B, et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest, 2005, 115(2): 268-281.
48. Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol, 2003, 4(4): 321-329.
49. Pino SC, O'Sullivan-Murphy B, Lidstone EA, et al. Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response. Cell Stress Chaperones, 2008, 13(4): 421-434.
50. Yoshimura FK, Luo X. Induction of endoplasmic reticulum stress in thymic lymphocytes by the envelope precursor polyprotein of a murine leukemia virus during the preleukemic period. J Virol, 2007, 81(8): 4374-4377.
51. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
52. Ryoo HD, Steller H. Unfolded protein response in Drosophila - Why another model can make it fly. Cell Cycle, 2007, 6(7): 830-835.
53. Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol, 2000, 20(18): 6755-6767.
54. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol, 2003, 23(21): 7448-7459.
55. Majors AK, Austin RC, de la Motte CA, et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. J Biol Chem, 2003, 278(47): 47223-47231.
56. Toth A, Nickson P, Mandl A, et al. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets, 2007, 7(3): 205-218.
57. Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr OpinCell Biol, 2006, 18(4): 444-452.
58. Alvarez P, Alvarado C, Puerto M, et al. Improvement of leukocyte functions in prematurely aging mice after five weeks of diet supplementation with polyphenol-rich cereals. Nutrition, 2006, 22(9): 913-921.
59. De la Fuente M, Del Rio M, Medina S. Changes with aging in the modulation by neuropeptide Y of murine peritoneal macrophage functions. J Neuroimmunol, 2001, 116(2): 156-167.
60. Sanchez A, Reeser JL, Lau HS, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr, 1973, 26(11): 1180-1184.
61. Falk W, Goodwin RH, Jr., Leonard EJ. A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods, 1980, 33(3): 239-247.
62. Don MJ, Liao JF, Lin LY, et al. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br J Pharmacol, 2007, 151(5): 638-646.
63. Ortega E, Forner MA, Barriga C. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol, 1997, 498( Pt 3): 729-734.
64. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
65. Bechill J, Chen Z, Brewer JW, et al. Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression. J Virol, 2008, 82(9): 4492-4501.
66. Bischof LJ, Kao CY, Los FC, et al. Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo. PLoS Pathog, 2008, 4(10): e1000176.
67. Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell, 2006, 124(3): 587-599.
68. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and deathdecisions. J Clin Invest, 2005, 115(10): 2656-2664.
69. Vitale A, Boston RS. Endoplasmic reticulum quality control and the unfolded protein response: insights from plants. Traffic, 2008, 9(10): 1581-1588.
70. Wheeler MC, Rizzi M, Sasik R, et al. KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity. J Immunol, 2008, 181(1): 256-264.
71. Hung JH, Su IJ, Lei HY, et al. Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem, 2004, 279(45): 46384-46392.
72. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
73. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. J Biol Chem, 2005, 280(40): 33917-33925.
74. Yarnamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha and XBP1. Developmental Cell, 2007, 13(3): 365-376.
75. Wu J, Rutkowski DT, Dubois M, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell, 2007, 13(3): 351-364.
76. Paschen W, Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium, 2005, 38(3-4): 409-415.
77. Goulding NJ. The molecular complexity of glucocorticoid actions in inflammation - a four-ring circus. Curr Opin Pharmacol, 2004, 4(6): 629-636.
78. Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Curr Opin Crit Care, 2005, 11(5): 449-453.
79. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med, 2005, 353(16): 1711-1723.
80. Saklatvala J. Glucocorticoids: do we know how they work? Arthritis Res, 2002, 4(3):146-150.
81. Drouin J, Sun YL, Chamberland M, et al. Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J, 1993, 12(1): 145-156.
82. Meyer T, Gustafsson JA, Carlstedt-Duke J. Glucocorticoid-dependent transcriptional repression of the osteocalcin gene by competitive binding at the TATA box. DNA Cell Biol, 1997, 16(8): 919-927.
83. Li C, Li Y, Liu H, et al. Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter. J Mol Endocrinol, 2008, 40(1): 3-12.
84. Gerritsen ME, Williams AJ, Neish AS, et al. CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A, 1997, 94(7): 2927-2932.
85. Sheppard KA, Phelps KM, Williams AJ, et al. Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1. J Biol Chem, 1998, 273(45): 29291-29294.
86. Lasa M, Abraham SM, Boucheron C, et al. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol, 2002, 22(22): 7802-7811.
87. Hermoso MA, Matsuguchi T, Smoak K, et al. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Mol Cell Biol, 2004, 24(11): 4743-4756.
88. Kassel O, Sancono A, Kratzschmar J, et al. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J, 2001, 20(24): 7108-7116.
89. Wang X, Nelin LD, Kuhlman JR, et al. The role of MAP kinase phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia. Life Sci, 2008, 83(19-20): 671-680.
90. Hiramatsu N, Kasai A, Hayakawa K, et al. Real-time detection and continuous monitoring of ER stress in vitro and in vivo by ES-TRAP: evidence for systemic,transient ER stress during endotoxemia. Nucleic Acids Res, 2006, 34(13): e93.
91. Goodall JC, Ellis L, Yeo GS, et al. Does HLA-B27 influence the monocyte inflammatory response to lipopolysaccharide? Rheumatology (Oxford), 2007, 46(2): 232-237.
92. Grivennikov SI, Tumanov AV, Liepinsh DJ, et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity, 2005, 22(1): 93-104.
93. Yokouchi M, Hiramatsu N, Hayakawa K, et al. Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem, 2008, 283(7): 4252-4260.
94. He S, Yaung J, Kim YH, et al. Endoplasmic reticulum stress induced by oxidative stress in retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol, 2008, 246(5): 677-683.
95. Holtz WA, Turetzky JM, Jong YJ, et al. Oxidative stress-triggered unfolded protein response is upstream of intrinsic cell death evoked by parkinsonian mimetics. J Neurochem, 2006, 99(1): 54-69.
96. Kozlov AV, Duvigneau JC, Miller I, et al. Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. Biochim Biophys Acta, 2009.
97. Gaut JR, Hendershot LM. The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol, 1993, 5(4): 589-595.
98. Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep, 2006, 7(9): 880-885.
99. van Anken E, Braakman I. Endoplasmic reticulum stress and the making of a professional secretory cell. Critical Reviews in Biochemistry and Molecular Biology, 2005, 40(5): 269-283.
100. Gass JN, Jiang HY, Wek RC, et al. The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Mol Immunol, 2008, 45(4): 1035-1043.
101. Tazi KA, Bieche I, Paradis V, et al. In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J Hepatol, 2007,46(6): 1075-1088.
102. Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res, 2005, 569(1-2): 29-63.
103. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab, 2002, 13(9): 373-380.
104. Kapoor A, Dunn E, Kostaki A, et al. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol, 2006, 572(Pt 1): 31-44.
105. Rivier J, Spiess J, Vale W. Characterization of rat hypothalamic corticotropin-releasing factor. Proc Natl Acad Sci U S A, 1983, 80(15): 4851-4855.
106. Venihaki M, Zhao J, Karalis KP. Corticotropin-releasing hormone deficiency results in impaired splenocyte response to lipopolysaccharide. J Neuroimmunol, 2003, 141(1-2): 3-9.
107. Aird F, Clevenger CV, Prystowsky MB, et al. Corticotropin-releasing factor mRNA in rat thymus and spleen. Proc Natl Acad Sci U S A, 1993, 90(15): 7104-7108.
108. Ekman R, Servenius B, Castro MG, et al. Biosynthesis of corticotropin-releasing hormone in human T-lymphocytes. J Neuroimmunol, 1993, 44(1): 7-13.
109. Muglia LJ, Jenkins NA, Gilbert DJ, et al. Expression of the mouse corticotropin-releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. J Clin Invest, 1994, 93(5): 2066-2072.
110. Dunn AJ, Berridge CW. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Brain Res Rev, 1990, 15(2): 71-100.
111. Venihaki M, Majzoub JA. Animal models of CRH deficiency. Front Neuroendocrinol, 1999, 20(2): 122-145.
112. Muglia L, Jacobson L, Dikkes P, et al. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature, 1995, 373(6513): 427-432.
113. Venihaki M, Carrigan A, Dikkes P, et al. Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency. Proc Natl AcadSci U S A, 2000, 97(13): 7336-7341.
114. Muglia LJ, Bae DS, Brown TT, et al. Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice. Am J Respir Cell Mol Biol, 1999, 20(2): 181-188.
115. Webster EL, Torpy DJ, Elenkov IJ, et al. Corticotropin-releasing hormone and inflammation. Ann N Y Acad Sci, 1998, 840: 21-32.
116. Karalis K, Muglia LJ, Bae D, et al. CRH and the immune system. J Neuroimmunol, 1997, 72(2): 131-136.
117. Vale W, Spiess J, Rivier C, et al. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 1981, 213(4514): 1394-1397.
118. Jessop DS, Harbuz MS, Lightman SL. CRH in chronic inflammatory stress. Peptides, 2001, 22(5): 803-807.
119. Patel S, Roelke CT, Rademacher DJ, et al. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology, 2004, 145(12): 5431-5438.
120. Rademacher DJ, Meier SE, Shi L, et al. Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology, 2008, 54(1): 108-116.
121. Maddali S, Stapleton PP, Freeman TA, et al. Neuroendocrine responses mediate macrophage function after trauma. Surgery, 2004, 136(5): 1038-1046.
122. Selye H, Fortier C. Adaptive reaction to stress. Psychosom Med, 1950, 12(3): 149-157.
123. Selye H. Endocrine reactions during stress. Curr Res Anesth Analg, 1956, 35(3): 182-193.
124. Selye H. Implications of stress concept. N Y State J Med, 1975, 75(12): 2139-2145.
125. DeBold CR, Sheldon WR, DeCherney GS, et al. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine corticotropin-releasing factor. J Clin Invest, 1984, 73(2): 533-538.
126. Van de Kar LD, Blair ML. Forebrain pathways mediating stress-induced hormonesecretion. Front Neuroendocrinol, 1999, 20(1): 1-48.
127. Dhabhar FS. Stress-induced enhancement of cell-mediated immunity. Ann N Y Acad Sci, 1998, 840: 359-372.
128. Zhou D, Kusnecov AW, Shurin MR, et al. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology, 1993, 133(6): 2523-2530.
129. Marin MT, Cruz FC, Planeta CS. Chronic restraint or variable stresses differently affect the behavior, corticosterone secretion and body weight in rats. Physiol Behav, 2007, 90(1): 29-35.
130. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95(10): 957-970.
131. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ, 2006, 13(3): 363-373.
132. Muglia LJ, Jacobson L, Weninger SC, et al. The physiology of corticotropin-releasing hormone deficiency in mice. Peptides, 2001, 22(5): 725-731.
133. Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol, 2003, 24(8): 444-448.
134. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol, 2005, 5(3): 243-251.
135. Kusnecov AW, Rabin BS. Stressor-induced alterations of immune function: mechanisms and issues. Int Arch Allergy Immunol, 1994, 105(2): 107-121.
136. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull, 2004, 130(4): 601-630.
137. Pruett SB. Quantitative aspects of stress-induced immunomodulation. Int Immunopharmacol, 2001, 1(3): 507-520.
138. Hermann G, Beck FM, Sheridan JF. Stress-induced glucocorticoid response modulates mononuclear cell trafficking during an experimental influenza viral infection. J Neuroimmunol, 1995, 56(2): 179-186.
139. Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking. Ann N Y Acad Sci, 2000, 917:876-893.
140. Dhabhar FS. Stress-induced augmentation of immune function--the role of stress hormones, leukocyte trafficking, and cytokines. Brain Behav Immun, 2002, 16(6): 785-798.
141. Dhabhar FS. Stress, leukocyte trafficking, and the augmentation of skin immune function. Ann N Y Acad Sci, 2003, 992: 205-217.
142. Chancellor-Freeland C, Zhu GF, Kage R, et al. Substance P and stress-induced changes in macrophages. Ann N Y Acad Sci, 1995, 771: 472-484.
143. Deak T, Meriwether JL, Fleshner M, et al. Evidence that brief stress may induce the acute phase response in rats. Am J Physiol, 1997, 273(6 Pt 2): R1998-2004.
144. Fleshner M, Nguyen KT, Cotter CS, et al. Acute stressor exposure both suppresses acquired immunity and potentiates innate immunity. Am J Physiol, 1998, 275(3 Pt 2): R870-878.
145. Campisi J, Fleshner M. Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J Appl Physiol, 2003, 94(1): 43-52.
146. Saint-Mezard P, Chavagnac C, Bosset S, et al. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol, 2003, 171(8): 4073-4080.
147. Harmsen AG, Turney TH. Inhibition of in vivo neutrophil accumulation by stress. Possible role of neutrophil adherence. Inflammation, 1985, 9(1): 9-20.
148. Shurin MR, Kusnecov A, Hamill E, et al. Stress-induced alteration of polymorphonuclear leukocyte function in rats. Brain Behav Immun, 1994, 8(2): 163-169.
149. Jain S, Stevenson JR. Enhancement by restraint stress of natural killer cell activity and splenocyte responsiveness to concanavalin A in Fischer 344 rats. Immunol Invest, 1991, 20(4): 365-376.
150. LeMay LG, Vander AJ, Kluger MJ. The effects of psychological stress on plasma interleukin-6 activity in rats. Physiol Behav, 1990, 47(5): 957-961.
151. Maes M, Hendriks D, Van Gastel A, et al. Effects of psychological stress on serum immunoglobulin, complement and acute phase protein concentrations in normal volunteers. Psychoneuroendocrinology, 1997, 22(6): 397-409.
152. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 2002, 415(6867): 92-96.
153. Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 2001, 107(7): 881-891.
154. Liou HC, Boothby MR, Finn PW, et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science, 1990, 247(4950): 1581-1584.
155. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 2001, 411(6836): 494-498.
156. Kirchhoff F. Silencing HIV-1 In Vivo. Cell, 2008, 134(4): 566-568.
157. Grimm D, Kay MA. Therapeutic application of RNAi: is mRNA targeting finally ready for prime time? J Clin Invest, 2007, 117(12): 3633-3641.
158. Morris KV, Rossi JJ. Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther, 2006, 13(6): 553-558.
159. Huang HY, Lee CC, Chiang BL. Small interfering RNA against interleukin-5 decreases airway eosinophilia and hyper-responsiveness. Gene Ther, 2008, 15(9): 660-667.
160. Kim YJ, Ahn J, Jeung SY, et al. Recombinant lentivirus-delivered short hairpin RNAs targeted to conserved coxsackievirus sequences protect against viral myocarditis and improve survival rate in an animal model. Virus Genes, 2008, 36(1): 141-146.
161. Lee CC, Huang HY, Chiang BL. Lentiviral-mediated GATA-3 RNAi decreases allergic airway inflammation and hyperresponsiveness. Mol Ther, 2008, 16(1): 60-65.
162. Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha and XBP1. Dev Cell, 2007, 13(3): 365-376.
163. Lin JH, Li H, Yasumura D, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science, 2007, 318(5852): 944-949.
164. Lin JH, Li H, Zhang Y, et al. Divergent effects of PERK and IRE1 signaling on cellviability. PLoS ONE, 2009, 4(1): e4170.
165. van Huizen R, Martindale JL, Gorospe M, et al. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem, 2003, 278(18): 15558-15564.
166. Sriburi R, Jackowski S, Mori K, et al. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol, 2004, 167(1): 35-41.
167. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
168. Yoshida H. Unconventional splicing of XBP-1 mRNA in the unfolded protein response. Antioxid Redox Signal, 2007, 9(12): 2323-2333.
169. Nishikawa S, Brodsky JL, Nakatsukasa K. Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem, 2005, 137(5): 551-555.
170. Ogawa S, Lozach J, Benner C, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell, 2005, 122(5): 707-721.
171. Wright AP, Zilliacus J, McEwan IJ, et al. Structure and function of the glucocorticoid receptor. J Steroid Biochem Mol Biol, 1993, 47(1-6): 11-19.
172. Butts CL, Sternberg EM. Neuroendocrine factors alter host defense by modulating immune function. Cell Immunol, 2008, 252(1-2): 7-15.
173. Elenkov IJ, Chrousos GP. Stress system--organization, physiology and immunoregulation. Neuroimmunomodulation, 2006, 13(5-6): 257-267.
174. Bowers SL, Bilbo SD, Dhabhar FS, et al. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun, 2008, 22(1): 105-113.
175. Rinehart JJ, Balcerzak SP, Sagone AL, et al. Effects of corticosteroids on human monocyte function. J Clin Invest, 1974, 54(6): 1337-1343.
176. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol, 2006, 102(1-5): 11-21.
177. Song IH, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments. Mol Cell Endocrinol, 2006, 246(1-2): 142-146.
178. Haller J, Mikics E, Makara GB. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front Neuroendocrinol, 2008, 29(2): 273-291.
179. Joels M, De Kloet ER. Coordinative mineralocorticoid and glucocorticoid receptor-mediated control of responses to serotonin in rat hippocampus. Neuroendocrinology, 1992, 55(3): 344-350.
180. Liu W, Wang J, Sauter NK, et al. Steroid receptor heterodimerization demonstrated in vitro and in vivo. Proc Natl Acad Sci U S A, 1995, 92(26): 12480-12484.
181. Trapp T, Holsboer F. Heterodimerization between mineralocorticoid and glucocorticoid receptors increases the functional diversity of corticosteroid action. Trends Pharmacol Sci, 1996, 17(4): 145-149.
182. Moguilewsky M, Philibert D. RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation. J Steroid Biochem, 1984, 20(1): 271-276.
183. Honer C, Nam K, Fink C, et al. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Mol Pharmacol, 2003, 63(5): 1012-1020.
1. Kitamura M. Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008, 12(5): 317-325.
2. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
3. Gaut JR, Hendershot LM. The modification and assembly of proteins in the endoplasmic reticulum. Curr Opin Cell Biol, 1993, 5(4): 589-595.
4. Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep, 2006, 7(9): 880-885.
5. Lee AS. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci, 2001, 26(8): 504-510.
6. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
7. Yoshida H. ER stress and diseases. FEBS J, 2007, 274(3): 630-658.
8. Fewell SW, Travers KJ, Weissman JS, et al. The action of molecular chaperones in the early secretory pathway. Annu Rev Genet, 2001, 35: 149-191.
9. Ellgaard L, Molinari M, Helenius A. Setting the standards: quality control in the secretory pathway. Science, 1999, 286(5446): 1882-1888.
10. Cid VJ, Duran A, del Rey F, et al. Molecular basis of cell integrity and morphogenesis in Saccharomyces cerevisiae. Microbiol Rev, 1995, 59(3): 345-386.
11. Mori K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell, 2000, 101(5): 451-454.
12. Ma Y, Hendershot LM. The unfolding tale of the unfolded protein response. Cell, 2001, 107(7): 827-830.
13. Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res, 2005, 569(1-2): 29-63.
14. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74:739-789.
15. Pahl HL. Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev, 1999, 79(3): 683-701.
16. Pakula TM, Laxell M, Huuskonen A, et al. The effects of drugs inhibiting protein secretion in the filamentous fungus Trichoderma reesei. Evidence for down-regulation of genes that encode secreted proteins in the stressed cells. J Biol Chem, 2003, 278(45): 45011-45020.
17. Martinez IM, Chrispeels MJ. Genomic analysis of the unfolded protein response in Arabidopsis shows its connection to important cellular processes. Plant Cell, 2003, 15(2): 561-576.
18. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by anendoplasmic-reticulum-resident kinase. Nature, 1999, 397(6716): 271-274.
19. Casagrande R, Stern P, Diehn M, et al. Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol Cell, 2000, 5(4): 729-735.
20. Friedlander R, Jarosch E, Urban J, et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol, 2000, 2(7): 379-384.
21. Travers KJ, Patil CK, Wodicka L, et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell, 2000, 101(3): 249-258.
22. Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol, 2004, 14(1): 20-28.
23. Ma Y, Hendershot LM. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell Stress Chaperones, 2002, 7(2): 222-229.
24. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell, 1999, 10(11): 3787-3799.
25. Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell, 2001, 107(7): 881-891.
26. Lee K, Tirasophon W, Shen X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev, 2002, 16(4): 452-466.
27. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature, 2002, 415(6867): 92-96.
28. Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol, 2000, 2(6): 326-332.
29. Shen J, Chen X, Hendershot L, et al. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell, 2002, 3(1): 99-111.
30. Kimata Y, Kimata YI, Shimizu Y, et al. Genetic evidence for a role of BiP/Kar2 thatregulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell, 2003, 14(6): 2559-2569.
31. Credle JJ, Finer-Moore JS, Papa FR, et al. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A, 2005, 102(52): 18773-18784.
32. Kimata Y, Ishiwata-Kimata Y, Ito T, et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J Cell Biol, 2007, 179(1): 75-86.
33. Wang XZ, Harding HP, Zhang Y, et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J, 1998, 17(19): 5708-5717.
34. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
35. Tirasophon W, Lee K, Callaghan B, et al. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev, 2000, 14(21): 2725-2736.
36. Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J, 1996, 15(12): 3028-3039.
37. Nishitoh H, Matsuzawa A, Tobiume K, et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev, 2002, 16(11): 1345-1355.
38. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science, 2000, 287(5453): 664-666.
39. Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol, 2006, 26(24): 9220-9231.
40. Maiuri MC, Zalckvar E, Kimchi A, et al. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol, 2007, 8(9): 741-752.
41. Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem, 2001,276(17): 13935-13940.
42. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol, 2007, 8(7): 519-529.
43. Clevers H. Inflammatory bowel disease, stress, and the endoplasmic reticulum. N Engl J Med, 2009, 360(7): 726-727.
44. Kokame K, Kato H, Miyata T. Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response. J Biol Chem, 2001, 276(12): 9199-9205.
45. Lee AH, Iwakoshi NN, Anderson KC, et al. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A, 2003, 100(17): 9946-9951.
46. Tirosh B, Iwakoshi NN, Glimcher LH, et al. Rapid turnover of unspliced Xbp-1 as a factor that modulates the unfolded protein response. J Biol Chem, 2006, 281(9): 5852-5860.
47. Yoshida H, Oku M, Suzuki M, et al. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. Journal of Cell Biology, 2006, 172(4): 565-575.
48. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol, 2003, 23(21): 7448-7459.
49. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 2004, 21(1): 81-93.
50. Shen Y, Hendershot LM. Identification of ERdj3 and OBF-1/BOB-1/OCA-B as direct targets of XBP-1 during plasma cell differentiation. J Immunol, 2007, 179(5): 2969-2978.
51. Lee AH, Scapa EF, Cohen DE, et al. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science, 2008, 320(5882): 1492-1496.
52. Sriburi R, Jackowski S, Mori K, et al. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol, 2004, 167(1): 35-41.
53. Liou HC, Boothby MR, Finn PW, et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science, 1990, 247(4950): 1581-1584.
54. Clauss IM, Gravallese EM, Darling JM, et al. In situ hybridization studies suggest a role for the basic region-leucine zipper protein hXBP-1 in exocrine gland and skeletal development during mouse embryogenesis. Dev Dyn, 1993, 197(2): 146-156.
55. Reimold AM, Etkin A, Clauss I, et al. An essential role in liver development for transcription factor XBP-1. Genes Dev, 2000, 14(2): 152-157.
56. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
57. Hetz C, Bernasconi P, Fisher J, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science, 2006, 312(5773): 572-576.
58. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol, 2008, 8(9): 663-674.
59. Gu F, Nguyen DT, Stuible M, et al. Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. J Biol Chem, 2004, 279(48): 49689-49693.
60. Hetz C, Glimcher L. The daily job of night killers: alternative roles of the BCL-2 family in organelle physiology. Trends in Cell Biology, 2008, 18(1): 38-44.
61. Shi Y, Vattem KM, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol, 1998, 18(12): 7499-7509.
62. Brewer JW, Diehl JA. PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc Natl Acad Sci U S A, 2000, 97(23): 12625-12630.
63. Harding HP, Zhang Y, Bertolotti A, et al. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell, 2000, 5(5): 897-904.
64. Clemens MJ. Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis. Prog Mol Subcell Biol, 2001, 27: 57-89.
65. Hamanaka RB, Bennett BS, Cullinan SB, et al. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded proteinresponse pathway. Mol Biol Cell, 2005, 16(12): 5493-5501.
66. Novoa I, Zeng H, Harding HP, et al. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol, 2001, 153(5): 1011-1022.
67. Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev, 2004, 18(24): 3066-3077.
68. Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell, 2000, 6(6): 1355-1364.
69. Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem, 2002, 277(15): 13045-13052.
70. van Huizen R, Martindale JL, Gorospe M, et al. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. J Biol Chem, 2003, 278(18): 15558-15564.
71. Bailey D, O'Hare P. Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid Redox Signal, 2007, 9(12): 2305-2321.
72. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 1997, 89(3): 331-340.
73. Haze K, Okada T, Yoshida H, et al. Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response. Biochem J, 2001, 355(Pt 1): 19-28.
74. Thuerauf DJ, Morrison L, Glembotski CC. Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction. J Biol Chem, 2004, 279(20): 21078-21084.
75. Adachi Y, Yamamoto K, Okada T, et al. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct, 2008, 33(1): 75-89.
76. Yarnamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 alpha andXBP1. Dev Cell, 2007, 13(3): 365-376.
77. Wu J, Rutkowski DT, Dubois M, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell, 2007, 13(3): 351-364.
78. Wang Y, Shen J, Arenzana N, et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem, 2000, 275(35): 27013-27020.
79. Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem, 1998, 273(50): 33741-33749.
80. Yoshida H, Okada T, Haze K, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol, 2000, 20(18): 6755-6767.
81. Roy B, Lee AS. The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res, 1999, 27(6): 1437-1443.
82. Gass JN, Gunn KE, Sriburi R, et al. Stressed-out B cells? Plasma-cell differentiation and the unfolded protein response. Trends in Immunology, 2004, 25(1): 17-24.
83. Yan W, Frank CL, Korth MJ, et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci U S A, 2002, 99(25): 15920-15925.
84. Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev, 1998, 12(7): 982-995.
85. Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004, 95(10): 957-970.
86. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest, 2005, 115(10): 2656-2664.
87. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ, 2006, 13(3): 363-373.
1. Kitamura M. Endoplasmic reticulum stress in the kidney. Clin Exp Nephrol, 2008, 12(5): 317-325.
2. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 1999, 13(10): 1211-1233.
3. Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature, 2001, 412(6844): 300-307.
4. Iwakoshi NN, Lee AH, Vallabhajosyula P, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol, 2003, 4(4): 321-329.
5. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity, 2004, 21(1): 81-93.
6. Gass JN, Gifford NM, Brewer JW. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J Biol Chem, 2002, 277(50): 49047-49054.
7. Tirosh B, Iwakoshi NN, Glimcher LH, et al. XBP-1 specifically promotes IgMsynthesis and secretion, but is dispensable for degradation of glycoproteins in primary B cells. J Exp Med, 2005, 202(4): 505-516.
8. Skalet AH, Isler JA, King LB, et al. Rapid B cell receptor-induced unfolded protein response in nonsecretory B cells correlates with pro- versus antiapoptotic cell fate. J Biol Chem, 2005, 280(48): 39762-39771.
9. Rush JS, Sweitzer T, Kent C, et al. Biogenesis of the endoplasmic reticulum in activated B lymphocytes: temporal relationships between the induction of protein N-glycosylation activity and the biosynthesis of membrane protein and phospholipid. Arch Biochem Biophys, 1991, 284(1): 63-70.
10. Wiest DL, Burkhardt JK, Hester S, et al. Membrane biogenesis during B cell differentiation: most endoplasmic reticulum proteins are expressed coordinately. J Cell Biol, 1990, 110(5): 1501-1511.
11. Zhang K, Wong HN, Song B, et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest, 2005, 115(2): 268-281.
12. Gass JN, Jiang HY, Wek RC, et al. The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Mol Immunol, 2008, 45(4): 1035-1043.
13. Iwakoshi NN, Pypaert M, Glimcher LH. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J Exp Med, 2007, 204(10): 2267-2275.
14. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol, 2008, 8(9): 663-674.
15. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature, 2008, 454(7203): 455-462.
16. Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci, 2000, 25(10): 502-508.
17. Tu BP, Weissman JS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol, 2004, 164(3): 341-346.
18. Tu BP, Weissman JS. The FAD- and O(2)-dependent reaction cycle of Ero1-mediated oxidative protein folding in the endoplasmic reticulum. Mol Cell, 2002, 10(5):983-994.
19. Cullinan SB, Zhang D, Hannink M, et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol, 2003, 23(20): 7198-7209.
20. Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell, 2003, 11(3): 619-633.
21. Mathers J, Fraser JA, McMahon M, et al. Antioxidant and cytoprotective responses to redox stress. Biochem Soc Symp, 2004, 71: 157-176.
22. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev, 2006, 38(4): 769-789.
23. Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem, 2004, 279(19): 20108-20117.
24. Sekine Y, Takeda K, Ichijo H. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med, 2006, 6(1): 87-97.
25. Hu P, Han Z, Couvillon AD, et al. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol, 2006, 26(8): 3071-3084.
26. Kaneko M, Niinuma Y, Nomura Y. Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biol Pharm Bull, 2003, 26(7): 931-935.
27. Deng J, Lu PD, Zhang Y, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol, 2004, 24(23): 10161-10168.
28. Jiang HY, Wek SA, McGrath BC, et al. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol, 2003, 23(16): 5651-5663.
29. Rius J, Guma M, Schachtrup C, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature, 2008, 453(7196): 807-811.
30. Pahl HL, Baeuerle PA. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B. J Virol, 1995, 69(3): 1480-1484.
31. Meyer M, Caselmann WH, Schluter V, et al. Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. EMBO J, 1992, 11(8): 2991-3001.
32. Pahl HL, Baeuerle PA. Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett, 1996, 392(2): 129-136.
33. Deniaud A, Sharaf el dein O, Maillier E, et al. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene, 2008, 27(3): 285-299.
34. Wu S, Tan M, Hu Y, et al. Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J Biol Chem, 2004, 279(33): 34898-34902.
35. Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science, 2000, 287(5453): 664-666.
36. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell, 2000, 103(2): 239-252.
37. Hayakawa K, Hiramatsu N, Okamura M, et al. Blunted activation of NF-kappaB and NF-kappaB-dependent gene expression by geranylgeranylacetone: involvement of unfolded protein response. Biochem Biophys Res Commun, 2008, 365(1): 47-53.
38. Takano Y, Hiramatsu N, Okamura M, et al. Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response. Biochem Biophys Res Commun, 2007, 360(2): 470-475.
39. Endo S, Hiramatsu N, Hayakawa K, et al. Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. Molecular Pharmacology, 2007, 72(5): 1337-1348.
40. Hayakawa K, Hiramatsu N, Okamura M, et al. Acquisition of anergy to proinflammatory cytokines in nonimmune cells through endoplasmic reticulum stress response: a mechanism for subsidence of inflammation. J Immunol, 2009, 182(2):1182-1191.
41. Devin A, Lin Y, Yamaoka S, et al. The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol, 2001, 21(12): 3986-3994.
42. Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell, 2000, 6(6): 1355-1364.
43. Brown MS, Ye J, Rawson RB, et al. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell, 2000, 100(4): 391-398.
44. Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell, 2006, 124(3): 587-599.
45. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol, 2003, 4(7): 517-529.
46. Gorlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal, 2006, 8(9-10): 1391-1418.
47. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxidants & Redox Signaling, 2007, 9(12): 2277-2293.
48. Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science, 1992, 258(5090): 1898-1902.
49. Uehara T, Nakamura T, Yao D, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature, 2006, 441(7092): 513-517.
50. Xu W, Liu L, Charles IG, et al. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol, 2004, 6(11): 1129-1134.
51. Xu KY, Huso DL, Dawson TM, et al. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci U S A, 1999, 96(2): 657-662.
52. Xue X, Piao JH, Nakajima A, et al. Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. J Biol Chem, 2005,280(40): 33917-33925.
53. Lin W, Harding HP, Ron D, et al. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol, 2005, 169(4): 603-612.
54. Feng B, Yao PM, Li Y, et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol, 2003, 5(9): 781-792.
55. Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest, 2002, 110(6): 851-860.
56. Kharroubi I, Ladriere L, Cardozo AK, et al. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology, 2004, 145(11): 5087-5096.
57. Zhou J, Werstuck GH, Lhotak S, et al. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation, 2004, 110(2): 207-213.
58. Yamamuro A, Yoshioka Y, Ogita K, et al. Involvement of endoplasmic reticulum stress on the cell death induced by 6-hydroxydopamine in human neuroblastoma SH-SY5Y cells. Neurochem Res, 2006, 31(5): 657-664.
59. Hotamisligil GS. Inflammation and metabolic disorders. Nature, 2006, 444(7121): 860-867.
60. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J Clin Invest, 2002, 110(10): 1389-1398.
61. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 2004, 306(5695): 457-461.
62. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science, 2006, 313(5790): 1137-1140.
63. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature, 2002, 420(6913): 333-336.
64. Aguirre V, Werner ED, Giraud J, et al. Phosphorylation of Ser307 in insulin receptorsubstrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem, 2002, 277(2): 1531-1537.
65. Tuncman G, Hirosumi J, Solinas G, et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci U S A, 2006, 103(28): 10741-10746.
66. Williams KJ, Tabas I. Atherosclerosis and inflammation. Science, 2002, 297(5581): 521-522.
67. Li Y, Schwabe RF, DeVries-Seimon T, et al. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem, 2005, 280(23): 21763-21772.
68. Gargalovic PS, Gharavi NM, Clark MJ, et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol, 2006, 26(11): 2490-2496.
69. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol, 2007, 208(1): 1-25.
70. Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell Death Differ, 2006, 13(3): 385-392.
71. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science, 2001, 292(5521): 1552-1555.
72. Nishitoh H, Kadowaki H, Nagai A, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev, 2008, 22(11): 1451-1464.
73. Wang HQ, Takahashi R. Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson's disease. Antioxid Redox Signal, 2007, 9(5): 553-561.
74. Silva RM, Ries V, Oo TF, et al. CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem, 2005, 95(4): 974-986.
75. Hetz C, Lee AH, Gonzalez-Romero D, et al. Unfolded protein response transcriptionfactor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci U S A, 2008, 105(2): 757-762.
76. Paschen W, Aufenberg C, Hotop S, et al. Transient cerebral ischemia activates processing of xbp1 messenger RNA indicative of endoplasmic reticulum stress. J Cereb Blood Flow Metab, 2003, 23(4): 449-461.
77. DeLegge MH, Smoke A. Neurodegeneration and inflammation. Nutr Clin Pract, 2008, 23(1): 35-41.
78. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med, 2006, 354(9): 942-955.
79. Lin W, Kemper A, Dupree JL, et al. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain, 2006, 129(Pt 5): 1306-1318.
80. Lin W, Bailey SL, Ho H, et al. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest, 2007, 117(2): 448-456.
81. Lees JR, Cross AH. A little stress is good: IFN-gamma, demyelination, and multiple sclerosis. J Clin Invest, 2007, 117(2): 297-299.
82. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008, 134(5): 743-756.
83. Lee AH, Chu GC, Iwakoshi NN, et al. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J, 2005, 24(24): 4368-4380.
84. Bertolotti A, Wang X, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin Invest, 2001, 107(5): 585-593.
85. Clevers H. Inflammatory bowel disease, stress, and the endoplasmic reticulum. N Engl J Med, 2009, 360(7): 726-727.
86. Kubota K, Niinuma Y, Kaneko M, et al. Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem, 2006, 97(5): 1259-1268.
87. Qi X, Hosoi T, Okuma Y, et al. Sodium 4-phenylbutyrate protects against cerebralischemic injury. Mol Pharmacol, 2004, 66(4): 899-908.
88. Liu L, Done SC, Khoshnoodi J, et al. Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. Hum Mol Genet, 2001, 10(23): 2637-2644.
89. Sawada N, Yao J, Hiramatsu N, et al. Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder. Lab Invest, 2008, 88(5): 553-563.
90. Takizawa S, Izuhara Y, Kitao Y, et al. A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia. Brain Res, 2007, 1183: 124-137.
91. Izuhara Y, Nangaku M, Takizawa S, et al. A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models. Nephrol Dial Transplant, 2008, 23(2): 497-509.
92. Tabata Y, Takano K, Ito T, et al. Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation. Am J Physiol Cell Physiol, 2007, 293(1): C411-418.
1. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol, 2006, 6(4): 318-328.
2. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev, 2000, 21(1): 55-89.
3. Lim HY, Muller N, Herold MJ, et al. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology, 2007, 122(1): 47-53.
4. Smyth GP, Stapleton PP, Freeman TA, et al. Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages. J Surg Res, 2004, 116(2): 253-261.
5. Long F, Wang YX, Liu L, et al. Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids, 2005, 70(1): 55-61.
6. Hoffmann JA, Kafatos FC, Janeway CA, et al. Phylogenetic perspectives in innate immunity. Science, 1999, 284(5418): 1313-1318.
7. Doherty DE, Haslett C, Tonnesen MG, et al. Human monocyte adherence: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endothelium. J Immunol, 1987, 138(6): 1762-1771.
8. Baggiolini M. Chemokines in pathology and medicine. J Intern Med, 2001, 250(2): 91-104.
9. Falk W, Goodwin RH, Jr., Leonard EJ. A 48-well micro chemotaxis assembly for rapid and accurate measurement of leukocyte migration. J Immunol Methods, 1980, 33(3): 239-247.
10. Don MJ, Liao JF, Lin LY, et al. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. Br J Pharmacol, 2007, 151(5): 638-646.
11. Lim LH, Flower RJ, Perretti M, et al. Glucocorticoid receptor activation reduces CD11b and CD49d levels on murine eosinophils: characterization and functional relevance. Am J Respir Cell Mol Biol, 2000, 22(6): 693-701.
12. Groyer A, Schweizer-Groyer G, Cadepond F, et al. Antiglucocorticosteroid effects suggest why steroid hormone is required for receptors to bind DNA in vivo but not in vitro. Nature, 1987, 328(6131): 624-626.
13. Butts CL, Sternberg EM. Neuroendocrine factors alter host defense by modulating immune function. Cell Immunol, 2008, 252(1-2): 7-15.
14. Elenkov IJ, Chrousos GP. Stress system--organization, physiology and immunoregulation. Neuroimmunomodulation, 2006, 13(5-6): 257-267.
15. Bowers SL, Bilbo SD, Dhabhar FS, et al. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav Immun, 2008, 22(1): 105-113.
16. Rinehart JJ, Balcerzak SP, Sagone AL, et al. Effects of corticosteroids on human monocyte function. J Clin Invest, 1974, 54(6): 1337-1343.
17. Ortega E, Forner MA, Barriga C. Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J Physiol, 1997, 498( Pt ): 729-734.
18. Baggiolini M, Loetscher P. Chemokines in inflammation and immunity. Immunol Today, 2000, 21(9): 418-420.
19. Taub DD, Oppenheim JJ. Chemokines, inflammation and the immune system. TherImmunol, 1994, 1(4): 229-246.
20. Woods J, Lu Q, Ceddia MA, et al. Special feature for the Olympics: effects of exercise on the immune system: exercise-induced modulation of macrophage function. Immunol Cell Biol, 2000, 78(5): 545-553.
21. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol, 2002, 20: 125-163.
22. Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of stress hormones on skin immune function. Proc Natl Acad Sci U S A, 1999, 96(3): 1059-1064.
23. Lyte M, Nelson SG, Thompson ML. Innate and adaptive immune responses in a social conflict paradigm. Clin Immunol Immunopathol, 1990, 57(1): 137-147.
24. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol, 2006, 102(1-5): 11-21.
25. Song IH, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments. Mol Cell Endocrinol, 2006, 246(1-2): 142-146.
26. Joels M, De Kloet ER. Coordinative mineralocorticoid and glucocorticoid receptor-mediated control of responses to serotonin in rat hippocampus. Neuroendocrinology, 1992, 55(3): 344-350.
27. Liu W, Wang J, Sauter NK, et al. Steroid receptor heterodimerization demonstrated in vitro and in vivo. Proc Natl Acad Sci U S A, 1995, 92(26): 12480-12484.
28. Trapp T, Holsboer F. Heterodimerization between mineralocorticoid and glucocorticoid receptors increases the functional diversity of corticosteroid action. Trends Pharmacol Sci, 1996, 17(4): 145-149.
29. Moguilewsky M, Philibert D. RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation. J Steroid Biochem, 1984, 20(1): 271-276.
30. Honer C, Nam K, Fink C, et al. Glucocorticoid receptor antagonism by cyproterone acetate and RU486. Mol Pharmacol, 2003, 63(5): 1012-1020.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |