JAK/STAT信号通路相关基因在系统性红斑狼疮发病中的作用研究
|
摘要
研究背景系统性红斑狼疮(systemic lupus erythematosus, SLE)是一种典型的自身免疫性疾病,其临床特征是产生大量自身抗体和多系统、器官受累。SLE的病因和发病机制至今尚未完全阐明,一般认为在遗传因素、环境因素等多种因素共同作用下引起机体免疫功能紊乱,产生多种免疫异常,导致大量致病性自身抗体和免疫复合物沉积于组织器官,从而引发相应的病理损害。SLE的免疫异常与细胞因子密切相关,国内外研究显示细胞因子及其免疫信号通路异常在SLE发病中起重要作用。
细胞因子是一类具有广泛生物学活性的小分子蛋白质,作为细胞信号传递分子,主要调节免疫应答、参与免疫细胞分化发育、介导炎症反应等。研究显示SLE患者体内存在多种细胞因子水平异常,其中干扰素(interferon, IFN),包括Ⅰ型IFN(α、β)及Ⅱ型IFN(γ)在SLE发病中的重要作用已经得到确认。
干扰素及其他细胞因子的生物学作用主要通过Janus激酶-信号转导和转录激活因子信号通路[Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway,JAK/STAT信号通路]来实现。JAK/STAT信号通路是继Ras途径之后又一重要的细胞因子信号转导通路,在细胞因子介导的免疫反应和免疫调控中具有重要的作用。国内外有研究显示SLE患者JAK/STAT信号通路相关信号分子如JAK1、TYK2、STAT1和STAT3的基因表达异常,酪氨酸激酶(2Tyrosine kinase 2,TYK2)、干扰素调节因子5(Interferon regulatory factor 5, IRF5)和信号转导和转录激活因子4(STAT4)的基因多态性与SLE的遗传易感性有关。最近有研究推测这些与细胞因子应答和产生相关的基因变异可能会影响免疫应答的阈值,导致自身抗体的产生和免疫异常。上述研究提示JAK/STAT通路中相关信号分子的基因水平表达异常和/或基因位点多态性在SLE的发病中可能起重要作用。
目前,关于JAK/STAT信号通路在SLE中的作用研究还很有限,而且多数研究仅限于单个基因或单个位点变异与SLE的关联性研究,缺乏针对免疫信号通路上所有功能相关基因的系统性研究。因此,系统地研究JAK/STAT信号通路相关信号分子表达水平与SLE的关联,将有助于进一步揭示SLE的发病机制、寻找潜在的诊断生物学标记和临床治疗靶点。
鉴于此,我们借助已建立的SLE遗传资源库,采用病例对照研究结合基因芯片技术,筛查通路上的差异表达基因。同时结合临床特征,分析这些基因的表达水平与SLE疾病活动度及脏器损伤之间的关系。
目的比较SLE患者和正常对照外周血白细胞中JAK/STAT信号通路相关基因的mRNA表达水平,筛选差异表达基因。同时结合临床资料,分析这些基因表达水平与SLE疾病活动度、脏器损伤及临床特征之间的关系。
方法病例来自两所三甲医院的SLE新发病例,以健康个体为正常对照;参照SLE疾病活动指数、美国风湿病学会1997年修订的SLE分类标准,设计问卷,收集患者的一般流行病学情况及临床和实验室资料。收集研究对象的血样,提取总RNA,逆转录合成cDNA,采用Q-PCR基因芯片技术检测JAK/STAT信号通路相关基因的mRNA表达水平。P<0.05且基因表达量上调或下调超过2倍标准判定为差异有统计学意义。
结果
(1)本研究共收集新发SLE患者25例,正常对照15例。SLE患者首发症状主要包括关节炎(60.0%)、颊部红斑或盘状红斑(56.0%)、肾脏损害(32.0%)等,多数人具有两个及以上首发症状。
(2)SLE患者与正常对照相比,共有16个基因表达异常。其中有12个基因的表达量显著上调,分别是SH2B2(2.46倍,P=0.0033)、CDKN1A(2.61倍,P=0.0005)、CRK(15.19倍,P<0.0001)、FAS(2.16倍,P=0.0005)、ISG15(11.49倍,P<0.0001)、IFNGR1(2.31倍,P=0.0006)、IRF9(2.06倍,P=0.0001)、JAK2(2.59倍,P<0.0001)、OAS1(3.75倍,P=0.0001)、OSM(3.00倍,P=0.0005)、SOCS3(2.00倍,P=0.0058)、SPI1(2.26倍,P<0.0001);有4个基因表达量明显下调,分别是FCER1A(2.93倍,P=0.0172)、PDGFRA(2.08倍,P=0.0018)、SIT1(2.14倍,P=0.0001)、RPL13A(2.29倍,P<0.0001)。
(3)狼疮肾炎患者与无狼疮肾炎的SLE患者相比,两组JAK / STAT信号通路相关基因mRNA的表达无明显差异。
(4)SLE活动性患者与非活动性患者相比,CDKN1A表达下调2.53倍(P=0.0146)。(5)SLE合并关节炎患者与无关节炎患者相比,SRC下调2.25倍(P=0.0230)。根据初步分析的这些基因生物学功能,主要包括:JAK/STAT蛋白分子(JAK2);细胞因子信号传导的抑制因子(SOCS3);细胞因子及其受体相关基因(IFNGR1);凋亡相关基因(Fas);干扰素相关基因(IRF9、ISG15和OAS1)、细胞周期、细胞生长增殖相关基因(CDNK1A、OSM和PDGFR)、免疫应答相关基因(FCER1A)及衔接蛋白基因(SH2B2、CRK、SIT1和SRC)等。
结论综上所述,本研究发现SLE患者JAK/STAT信号通路上多个环节的多个相关基因表达水平发生了改变。这些基因涉及信号转导、细胞凋亡、转录调节及免疫应答等多方面功能,提示JAK/STAT信号通路可能是SLE发病的重要免疫调控信号通路之一。表达水平异常的基因可能参与了SLE的病理过程且可能与疾病活动性及合并关节炎有关,可作为SLE候选易感基因。因此,深入、系统地研究JAK/STAT信号通路在SLE中的作用将为进一步阐明SLE的发病机制和开发分子诊断标志及药物靶标提供线索。
Background Systemic lupus erythematosus(SLE) is prototype of autoimmune disease characterized by high level of autoantibody production and multiple organ systems involvement. The etiology and pathogenesis of SLE has not yet been completely clarified. It is thought that a complex interaction of genetic and environmental factors may contribute to immune disorder in the pathogenesis of SLE, resulting in a variety of immune abnormalities which along with a large number of autoantibodies and immune complex deposition to trigger corresponding pathological damages.The immune abnormalities in SLE was found to be closely correlated to cytokines and researches showed that the abnormalities of cytokines and its immune signaling pathway play a key role in the pathogenesis of SLE.
Cytokines are small molecular proteins with broad biological activities. As cell signaling molecules, cytokines have an important effect on the regulation of the immune response, immune cell differentiation and development and inflammatory response. Studies have shown that abnormal expression of various cytokines was observed in SLE patients. Among these cytokines, the role of interferon (IFN), including type I interferon (IFN-α/β) and typeⅡinterferon (IFN-γ), in the pathogenesis of SLE have been confirmed.
The biological effects of IFNs and other cytokines are mainly mediated through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway which is one major cytokine signal transduction pathway playing an important role in cytokine-mediated immune response and immune regulation.
Studies have shown that abnormal gene expression of some JAK/STAT signaling pathway components such as JAK1, TYK2, STAT1and STAT3, was observed in SLE patients. The gene polymorphism of TYK2, IRF5 and STAT4 was also found to be associated with SLE genetic susceptibility. Recent studies have suggested that these gene variants linked to SLE might alter thresholds for immune response, resulting in the production of autoantibodies and immune abnormalities. These studies indicated that abnormal gene expression and gene polymorphism of JAK/STAT signaling pathway components might play an important role in the pathogenesis of SLE.
However, little is known about the role of JAK/STAT signaling pathway in SLE at present. Most studies were focused on the association study of a single gene or locus variants with SLE susceptibility, whereas the systemic study on all functional genes related to one immune signaling pathway was very limited. Therefore, the study of the expression of the signaling pathway related genes in SLE would help to further reveal the pathogenesis of SLE and develop new potential diagnostic biomarkers and therapeutic targets.
Thus, on the basis of SLE genetic resources, our study adopted case-control design and gene chip technology to screen the differentially expressed genes of JAK/STAT signaling pathway and analyze the relationship among the gene expression levels and SLE disease activity and organ damages.
Objective To identify the differentially expressed genes of JAK/STAT signaling pathway by comparing the mRNA expression levels of peripheral leukocytes between SLE patients and normal controls. Combined with clinical data,the relationship among the gene expression levels and SLE disease activity and organ damages were further analyzed.
Methods SLE patients were selected from two hospitals, and normal healthy volunteers were recruited as controls. General epidemiological information, the data of clinical manifestations and clinical laboratory indexes were collected by self-designed questionnaire according to the SLE disease activity index (SLEDAI) and the diagnostic and classification criteria. The total RNA was extracted from peripheral leukocytes of the collected blood samples and reversely transcribed in cDNA. Real-time quantitative PCR was used to detect the mRNA expression level of JAK/STAT signaling pathway related genes between SLE patients and normal controls. A p value less than 0.05 and a mean difference equal to or greater than 2-fold were considered statistically significant.
Results
(1) 25 new onset patients with SLE and 15 normal controls were collected in the present study. The most common initial symptoms in SLE patients were arthritis (60.0%),disciod erythema (56.0%) , kidney damage (32.0%),etc. Most patients had two or more symptoms.
(2) In total, we identified 16 candidate genes that were differentially expressed between SLE patients and normal controls. Of these 16 genes, 12 genes (SH2B2, CDKN1A, CRK, FAS, ISG15, IFNGR1、IRF9, JAK2, OAS1, OSM, SOCS3, SPI1)were up-regulated and 8 genes (FCER1A, PDGFRA, SIT1, RPL13A) were down-regulated in SLE patients.
(2) The genes expression has no significant difference between lupus nephritis patients and SLE patients without lupus nephritis.
(3) The expression of CDKN1A has significantly decreased by 2.53 times in active SLE patients compared with inactive SLE patients.
(4) The expression of SRC has significantly decreased by 2.25 times in SLE patients with arthritis compared with SLE patients without arthritis.
According to the biological function of these genes, the 16 genes contained JAK and STAT protein molecules (JAK2), negative regulators of the JAK/ STAT pathway (SOCS3), cytokines and receptors (IFNGR1), apoptosis-related genes (FAS), interferon-related gene (IRF9, ISG15 and OAS1), cell cycle and proliferation-related genes (CDNK1A, OSM and PDGFR), immune response genes (FCER1A) and adaptor protein molecules (SH2B2, CRK, SIT1 and SRC).
Conclusion In summary, our study showed that the expression levels of multiple genes related to JAK/STAT signaling pathway were significantly altered in SLE patients. These genes are involved in various functions, including signal transduction, apoptosis, transcriptional regulation, immune responses and so on, suggesting that JAK / STAT signaling pathway may be an important immune regulatory pathway in the pathogenesis of SLE and the abnormally expressed genes, as candidate susceptibility genes for SLE, might be involved in the pathogenesis of SLE and related to disease activity and lupus arthritis. Therefore, an in-depth, systemic study of the role of JAK/STAT signaling pathway in SLE might provide clues for elucidating the pathogenesis of SLE and developing potential diagnostic biomarkers and therapeutic targets.
细胞因子是一类具有广泛生物学活性的小分子蛋白质,作为细胞信号传递分子,主要调节免疫应答、参与免疫细胞分化发育、介导炎症反应等。研究显示SLE患者体内存在多种细胞因子水平异常,其中干扰素(interferon, IFN),包括Ⅰ型IFN(α、β)及Ⅱ型IFN(γ)在SLE发病中的重要作用已经得到确认。
干扰素及其他细胞因子的生物学作用主要通过Janus激酶-信号转导和转录激活因子信号通路[Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway,JAK/STAT信号通路]来实现。JAK/STAT信号通路是继Ras途径之后又一重要的细胞因子信号转导通路,在细胞因子介导的免疫反应和免疫调控中具有重要的作用。国内外有研究显示SLE患者JAK/STAT信号通路相关信号分子如JAK1、TYK2、STAT1和STAT3的基因表达异常,酪氨酸激酶(2Tyrosine kinase 2,TYK2)、干扰素调节因子5(Interferon regulatory factor 5, IRF5)和信号转导和转录激活因子4(STAT4)的基因多态性与SLE的遗传易感性有关。最近有研究推测这些与细胞因子应答和产生相关的基因变异可能会影响免疫应答的阈值,导致自身抗体的产生和免疫异常。上述研究提示JAK/STAT通路中相关信号分子的基因水平表达异常和/或基因位点多态性在SLE的发病中可能起重要作用。
目前,关于JAK/STAT信号通路在SLE中的作用研究还很有限,而且多数研究仅限于单个基因或单个位点变异与SLE的关联性研究,缺乏针对免疫信号通路上所有功能相关基因的系统性研究。因此,系统地研究JAK/STAT信号通路相关信号分子表达水平与SLE的关联,将有助于进一步揭示SLE的发病机制、寻找潜在的诊断生物学标记和临床治疗靶点。
鉴于此,我们借助已建立的SLE遗传资源库,采用病例对照研究结合基因芯片技术,筛查通路上的差异表达基因。同时结合临床特征,分析这些基因的表达水平与SLE疾病活动度及脏器损伤之间的关系。
目的比较SLE患者和正常对照外周血白细胞中JAK/STAT信号通路相关基因的mRNA表达水平,筛选差异表达基因。同时结合临床资料,分析这些基因表达水平与SLE疾病活动度、脏器损伤及临床特征之间的关系。
方法病例来自两所三甲医院的SLE新发病例,以健康个体为正常对照;参照SLE疾病活动指数、美国风湿病学会1997年修订的SLE分类标准,设计问卷,收集患者的一般流行病学情况及临床和实验室资料。收集研究对象的血样,提取总RNA,逆转录合成cDNA,采用Q-PCR基因芯片技术检测JAK/STAT信号通路相关基因的mRNA表达水平。P<0.05且基因表达量上调或下调超过2倍标准判定为差异有统计学意义。
结果
(1)本研究共收集新发SLE患者25例,正常对照15例。SLE患者首发症状主要包括关节炎(60.0%)、颊部红斑或盘状红斑(56.0%)、肾脏损害(32.0%)等,多数人具有两个及以上首发症状。
(2)SLE患者与正常对照相比,共有16个基因表达异常。其中有12个基因的表达量显著上调,分别是SH2B2(2.46倍,P=0.0033)、CDKN1A(2.61倍,P=0.0005)、CRK(15.19倍,P<0.0001)、FAS(2.16倍,P=0.0005)、ISG15(11.49倍,P<0.0001)、IFNGR1(2.31倍,P=0.0006)、IRF9(2.06倍,P=0.0001)、JAK2(2.59倍,P<0.0001)、OAS1(3.75倍,P=0.0001)、OSM(3.00倍,P=0.0005)、SOCS3(2.00倍,P=0.0058)、SPI1(2.26倍,P<0.0001);有4个基因表达量明显下调,分别是FCER1A(2.93倍,P=0.0172)、PDGFRA(2.08倍,P=0.0018)、SIT1(2.14倍,P=0.0001)、RPL13A(2.29倍,P<0.0001)。
(3)狼疮肾炎患者与无狼疮肾炎的SLE患者相比,两组JAK / STAT信号通路相关基因mRNA的表达无明显差异。
(4)SLE活动性患者与非活动性患者相比,CDKN1A表达下调2.53倍(P=0.0146)。(5)SLE合并关节炎患者与无关节炎患者相比,SRC下调2.25倍(P=0.0230)。根据初步分析的这些基因生物学功能,主要包括:JAK/STAT蛋白分子(JAK2);细胞因子信号传导的抑制因子(SOCS3);细胞因子及其受体相关基因(IFNGR1);凋亡相关基因(Fas);干扰素相关基因(IRF9、ISG15和OAS1)、细胞周期、细胞生长增殖相关基因(CDNK1A、OSM和PDGFR)、免疫应答相关基因(FCER1A)及衔接蛋白基因(SH2B2、CRK、SIT1和SRC)等。
结论综上所述,本研究发现SLE患者JAK/STAT信号通路上多个环节的多个相关基因表达水平发生了改变。这些基因涉及信号转导、细胞凋亡、转录调节及免疫应答等多方面功能,提示JAK/STAT信号通路可能是SLE发病的重要免疫调控信号通路之一。表达水平异常的基因可能参与了SLE的病理过程且可能与疾病活动性及合并关节炎有关,可作为SLE候选易感基因。因此,深入、系统地研究JAK/STAT信号通路在SLE中的作用将为进一步阐明SLE的发病机制和开发分子诊断标志及药物靶标提供线索。
Background Systemic lupus erythematosus(SLE) is prototype of autoimmune disease characterized by high level of autoantibody production and multiple organ systems involvement. The etiology and pathogenesis of SLE has not yet been completely clarified. It is thought that a complex interaction of genetic and environmental factors may contribute to immune disorder in the pathogenesis of SLE, resulting in a variety of immune abnormalities which along with a large number of autoantibodies and immune complex deposition to trigger corresponding pathological damages.The immune abnormalities in SLE was found to be closely correlated to cytokines and researches showed that the abnormalities of cytokines and its immune signaling pathway play a key role in the pathogenesis of SLE.
Cytokines are small molecular proteins with broad biological activities. As cell signaling molecules, cytokines have an important effect on the regulation of the immune response, immune cell differentiation and development and inflammatory response. Studies have shown that abnormal expression of various cytokines was observed in SLE patients. Among these cytokines, the role of interferon (IFN), including type I interferon (IFN-α/β) and typeⅡinterferon (IFN-γ), in the pathogenesis of SLE have been confirmed.
The biological effects of IFNs and other cytokines are mainly mediated through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway which is one major cytokine signal transduction pathway playing an important role in cytokine-mediated immune response and immune regulation.
Studies have shown that abnormal gene expression of some JAK/STAT signaling pathway components such as JAK1, TYK2, STAT1and STAT3, was observed in SLE patients. The gene polymorphism of TYK2, IRF5 and STAT4 was also found to be associated with SLE genetic susceptibility. Recent studies have suggested that these gene variants linked to SLE might alter thresholds for immune response, resulting in the production of autoantibodies and immune abnormalities. These studies indicated that abnormal gene expression and gene polymorphism of JAK/STAT signaling pathway components might play an important role in the pathogenesis of SLE.
However, little is known about the role of JAK/STAT signaling pathway in SLE at present. Most studies were focused on the association study of a single gene or locus variants with SLE susceptibility, whereas the systemic study on all functional genes related to one immune signaling pathway was very limited. Therefore, the study of the expression of the signaling pathway related genes in SLE would help to further reveal the pathogenesis of SLE and develop new potential diagnostic biomarkers and therapeutic targets.
Thus, on the basis of SLE genetic resources, our study adopted case-control design and gene chip technology to screen the differentially expressed genes of JAK/STAT signaling pathway and analyze the relationship among the gene expression levels and SLE disease activity and organ damages.
Objective To identify the differentially expressed genes of JAK/STAT signaling pathway by comparing the mRNA expression levels of peripheral leukocytes between SLE patients and normal controls. Combined with clinical data,the relationship among the gene expression levels and SLE disease activity and organ damages were further analyzed.
Methods SLE patients were selected from two hospitals, and normal healthy volunteers were recruited as controls. General epidemiological information, the data of clinical manifestations and clinical laboratory indexes were collected by self-designed questionnaire according to the SLE disease activity index (SLEDAI) and the diagnostic and classification criteria. The total RNA was extracted from peripheral leukocytes of the collected blood samples and reversely transcribed in cDNA. Real-time quantitative PCR was used to detect the mRNA expression level of JAK/STAT signaling pathway related genes between SLE patients and normal controls. A p value less than 0.05 and a mean difference equal to or greater than 2-fold were considered statistically significant.
Results
(1) 25 new onset patients with SLE and 15 normal controls were collected in the present study. The most common initial symptoms in SLE patients were arthritis (60.0%),disciod erythema (56.0%) , kidney damage (32.0%),etc. Most patients had two or more symptoms.
(2) In total, we identified 16 candidate genes that were differentially expressed between SLE patients and normal controls. Of these 16 genes, 12 genes (SH2B2, CDKN1A, CRK, FAS, ISG15, IFNGR1、IRF9, JAK2, OAS1, OSM, SOCS3, SPI1)were up-regulated and 8 genes (FCER1A, PDGFRA, SIT1, RPL13A) were down-regulated in SLE patients.
(2) The genes expression has no significant difference between lupus nephritis patients and SLE patients without lupus nephritis.
(3) The expression of CDKN1A has significantly decreased by 2.53 times in active SLE patients compared with inactive SLE patients.
(4) The expression of SRC has significantly decreased by 2.25 times in SLE patients with arthritis compared with SLE patients without arthritis.
According to the biological function of these genes, the 16 genes contained JAK and STAT protein molecules (JAK2), negative regulators of the JAK/ STAT pathway (SOCS3), cytokines and receptors (IFNGR1), apoptosis-related genes (FAS), interferon-related gene (IRF9, ISG15 and OAS1), cell cycle and proliferation-related genes (CDNK1A, OSM and PDGFR), immune response genes (FCER1A) and adaptor protein molecules (SH2B2, CRK, SIT1 and SRC).
Conclusion In summary, our study showed that the expression levels of multiple genes related to JAK/STAT signaling pathway were significantly altered in SLE patients. These genes are involved in various functions, including signal transduction, apoptosis, transcriptional regulation, immune responses and so on, suggesting that JAK / STAT signaling pathway may be an important immune regulatory pathway in the pathogenesis of SLE and the abnormally expressed genes, as candidate susceptibility genes for SLE, might be involved in the pathogenesis of SLE and related to disease activity and lupus arthritis. Therefore, an in-depth, systemic study of the role of JAK/STAT signaling pathway in SLE might provide clues for elucidating the pathogenesis of SLE and developing potential diagnostic biomarkers and therapeutic targets.
引文
1.叶冬青(主编).红斑狼疮.北京:人民卫生出版社, 2006.
2. Louren?o EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med. 2009; 9(3):242-54.
3. Meyer O. Interferons and autoimmune disorders. Joint Bone Spine. 2009; 76(5):464-73.
4. Dall’era MC, Cardarelli PM, Preston BT, Witte A, Davis JC Jr. Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis 2005; 64(12): 1692-97.
5. Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, Tsao BP. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006; 54(9):2951-62.
6.吴元胜,范瑞强,陈达灿,禤国维.基因芯片技术分析系统性红斑狼疮患者外周血白细胞基因表达谱的初步研究.第一军医大学学报. 2005; 25(8):929-34.
7. Nicoletti F, Di Marco R, Zaccone P, Xiang M, Magro G, Grasso S, Morrone S, Santoni A, Shoenfeld Y, Garotta G, Meroni P. Dichotomic effects of IFN-gamma on the development of systemic lupus erythematosus-like syndrome in MRL-lpr / lpr mice. Eur J Immunol. 2000; 30(2):438-47.
8. Arbouzova NI, Zeidler MP. JAK/STAT signaling in Drosophila: insights into conserved regulatory and cellular functions. Development. 2006; 133(14):2605-16.
9. O'Shea JJ, Notarangelo LD, Johnston JA, Candotti F. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency. J Clin Immunol. 1997; 17(6):431-47.
10.张树民. JAK-STAT和免疫系统的关系.国外医学免疫学分册. 1999; 22(5):294-7.
11. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of negative regulators of signal transduction. J Leukoc Biol. 1998; 63(6):665-8.
12. Harley JB, Kelly JA, Kaufman KM. Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol. 2006; 28(2):119-30.
13. Rhodes B, Vyse TJ. The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology (Oxford). 2008; 7(11):1603-11.
14. Graham RR, Hom G, Ortmann W, Behrens TW. Review of recent genome-wide association scans in lupus. J Intern Med. 2009; 265(6):680-8.
15. Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res. 2010; 155(3):109-17.
16.董静,蒋艳霞,刘爱国,王少春,杨清锐,张源潮. MRL/lpr小鼠肾组织JAK/STAT信号转导途径的表达和雷帕霉素对其表达的影响.中华微生物学和免疫学杂志. 2007; 27(6):490-4.
17. Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, Jacob CO. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. JImmunol. 2003; 170(9):4818-25.
18. Valencia-Pacheco G, Layseca-Espinosa E, Ni?o-Moreno P, Portales-Pérez DP, Baranda L, Rosenstein Y, Abud-Mendoza C, González-Amaro R. Expression and function of IL-10R in mononuclear cells from patients with systemic lupus erythematosus. Scand J Rheumatol. 2006; 35(5):368-78.
19. Hellquist A, J?rvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D'Amato M, Saarialho-Kere U, Kere J. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009; 36(8):1631-8.
20. Sigurdsson S, Nordmark G, G?ring HH, Lindroos K, Wiman AC, Sturfelt G, J?nsen A, Rantap??-Dahlqvist S, M?ller B, Kere J, Koskenmies S, Widén E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, R?nnblom L, Syv?nen AC. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet. 2005; 76(3):528-37.
21. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007; 40(1):1-8.
22.黎莉,陈顺乐,沈南,鲍春德,钱捷,叶萍,顾越英,王元.系统性红斑狼疮初发患者Th细胞异常分化相关分子基因表达研究.中华风湿病学杂志. 2003; 7(3):133-8.
23. Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, Ye DQ. A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol. 2010. [Epub ahead of print]
24. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, KastnerDL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007; 357(10):977-86.
25. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, Gao F, Zhang PL, Guo Q, Li B, Gao M, Xiao FL, Quan C, Zhang C, Zhang Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009; 41(11):1234-7.
26. Neubauer H, Cumano A, Müller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998, 93(3):397-409.
27.杨馨,李继书,杨慎峭,张新星,张天生,周海燕,刘旭光.艾灸对实验性类风湿性关节炎家兔滑膜细胞JAK-STAT信号通路影响的研究.针刺研究. 2007; 32(4):75-82.
28. Bright JJ, Du C, Sriram S. Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 1999; 162(10):6255-62.
29.高薇,杨娉婷,沈晖,鲁静,肖卫国,赵丽娟.阻断JAK2-STAT信号通路对大鼠类风湿关节炎治疗作用的实验研究.中国实用内科杂志. 2007;27(11):872-5.
30. Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol. 2008; 19(4):414-22.
31. Song MM, Shuai K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferativeactivities. J Biol Chem. 1998; 273(52):35056-62.
32. Dong J, Wang QX, Zhou CY, Ma XF, Zhang YC. Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus. 2007; 16(2):101-9.
33. Tsao JT, Kuo CC, Lin SC. The analysis of CIS, SOCS1, SOSC2 and SOCS3 transcript levels in peripheral blood mononuclear cells of systemic lupus erythematosus and rheumatoid arthritis patients. Clin Exp Med. 2008; 8(4):179-85.
34. Losana G, Rigamonti L, Borghi I, Assenzio B, Ariotti S, Jouanguy E, Altare F, Forni G, Casanova JL, Novelli F. Requirement for both IL-12 and IFN-gamma signaling pathways in optimal IFN-gamma production by human T cells. Eur J Immunol. 2002; 32(3):693-700.
35. Haas C, Ryffel B, Le Hir M. IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW)F1 mice. J Immunol. 1998; 160(8):3713-8.
36. Tanaka Y, Nakashima H, Hisano C, Kohsaka T, Nemoto Y, Niiro H, Otsuka T, Otsuka T, Imamura T, Niho Y. Association of the interferon-gamma receptor variant (Val14Met) with systemic lupus erythematosus. Immunogenetics. 1999; 49(4):266-71.
37. Xu Y, Chen ZQ, Li YM, Gong JQ, Li AS, Chen M, Liu J. Correlation between some Th1 and Th2 cytokine receptor gene polymorphisms and systemic lupus erythematosus in Chinese patients. Int J Dermatol. 2007; 46(11):1129-35.
38. Ozmen L, Roman D, Fountoulakis M, Schmid G, Ryffel B, Garotta G. Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. Eur J Immunol. 1995; 25(1):6-12.
39. Lawson BR, Prud'homme GJ, Chang Y, Gardner HA, Kuan J, Kono DH, Theofilopoulos AN. Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc. J Clin Invest. 2000; 106(2):207-15.
40. Randhawa SR, Chahine BG, Lowery-Nordberg M, Cotelingam JD, Casillas AM. Underexpression and overexpression of Fas and Fas ligand: a double-edged sword. Ann Allergy Asthma Immunol. 2010; 104(4):286-92.
41. Battle TE, Frank DA.The role of STATs in apoptosis. Curr Mol Med. 2002; 2(4):381-92.
42. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS. 2006; 114(9):619-25.
43. Desrivières S, Kunz C, Barash I, Vafaizadeh V, Borghouts C, Groner B.The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition. J Mammary Gland Biol Neoplasia. 2006; 11(1):75-87.
44. Suk K, Kim S, Kim YH, Kim KA, Chang I, Yagita H, Shong M, Lee MS. IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol. 2001; 166(7):4481-9.
45. Cousens LP, Goulette FA, Darnowski JW. JAK-mediated signaling inhibits Fas ligand-induced apoptosis independent of de novo protein synthesis. J Immunol. 2005; 174(1):320-7.
46. Li LH, Li WX, Wu O, Zhang GQ, Pan HF, Li XP, Xu JH, Dai H, Ye DQ. Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus: relation to the organ damage and lymphocytes apoptosis. Mol Biol Rep. 2009; 36(8):2047-52.
47. Araste JM, Sarvestani EK, Aflaki E, Amirghofran Z. Fas gene polymorphisms in systemic lupus erythematosus and serum levels of some apoptosis-related molecules. Immunol Invest. 2010; 39(1):27-38.
48.叶霜,沈南,顾越英,陈顺乐,韩光明,冯修高,冯学兵,陈兴国,华晶,黄文群,王元,鲍春德.系统性红斑狼疮的基因表达谱及其免疫调控通路的研究.中华风湿病学杂志. 2002; 6(6):411-16.
49. Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, Tsao BP. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006; 54(9):2951-62.
50. Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, Peterson LF, Shuai K, Zhang DE. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev. 2003; 17(4):455-60.
51. Brand S, Zitzmann K, Dambacher J, Beigel F, Olszak T, Vlotides G, Eichhorst ST, G?ke B, Diepolder H, Auernhammer CJ. SOCS-1 inhibits expression of the antiviral proteins 2',5'-OAS and MxA induced by the novel interferon-lambdas IL-28A and IL-29. Biochem Biophys Res Commun. 2005; 331(2):543-8.
52. Preble OT, Rothko K, Klippel JH, Friedman RM, Johnston MI. Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon. J Exp Med. 1983; 157(6):2140-6.
53. Jeon YJ, Yoo HM, Chung CH. ISG15 and immune diseases. Biochim Biophys Acta. 2010; 1802(5):485-96.
54. Ozato K, Tailor P, Kubota T. The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem. 2007; 282(28):20065-9.
55.钱捷,沈南,郭桂梅,万年红,林燕,黄新芳,吴慧,陈顺乐.系统性红斑狼疮患者干扰素调节因子IRF1 IRF4 IRF8基因表达的研究.中华风湿病学杂志,2006;10(9):513-6.
56. Reilly CM, Olgun S, Goodwin D, Gogal RM Jr, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS. Interferon regulatory factor-1 gene deletion decreasesglomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006; 36(5):1296-308.
57. Akahoshi M, Nakashima H, Sadanaga A, Miyake K, Obara K, Tamari M, Hirota T, Matsuda A, Shirakawa T. Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus. Lupus. 2008; 17(6):568-74.
58. Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008; 58(8):2481-7.
59. Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, Merrill JT, James JA, Frank SG, Reams E, Brown EE, Gibson AW, Marion MC, Langefeld CD, Li QZ, Karp DR, Wakeland EK, Petri M, Ramsey-Goldman R, Reveille JD, ViláLM, Alarcón GS, Kimberly RP, Harley JB, Edberg JC. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun. 2008; 9(3):187-94.
60. Tsuno T, Mejido J, Zhao T, Schmeisser H, Morrow A, Zoon KC. IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha. J Immunother. 2009;32(8):803-16.
61. Coqueret O, Gascan H. Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem. 2000; 275(25):18794-800.
62. Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, Hamilton SR, Amin HM. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005; 167(4):969-80.
63. Tanaka M, Miyajima A. Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol. 2003; 149:39-52.
64. Liu J, Hadjokas N, Mosley B, Estrov Z, Spence MJ, Vestal RE. Oncostatin M-specific receptor expression and function in regulating cell proliferation ofnormal and malignant mammary epithelial cells. Cytokine. 1998; 10(4):295-302.
65. Radtke S, Hermanns HM, Haan C, Schmitz-Van De Leur H, Gascan H, Heinrich PC, Behrmann I. Novel role of Janus kinase 1 in the regulation of oncostatin M receptor surface expression. J Biol Chem.2002; 277 (13):11297-305.
66. Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol. 1996; 16(4):1759-69.
67. Floege J, van Roeyen C, Boor P, Ostendorf T. The role of PDGF-D in mesangioproliferative glomerulonephritis. Contrib Nephrol. 2007; 157:153-8.
68. Hirai T, Masaki T, Kuratsune M, Yorioka N, Kohno N. PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation. Clin Exp Immunol. 2006; 144(2):353-61.
69.陆青,沈南,陈顺乐,倪旭鸣. NZB/W狼疮鼠体外IFN-α信号调控网络研究.现代免疫学.2008; 28(4):305-11.
70.郑丰,刘志红,周虹,张京红,钱斌,唐政,陈慧平,黎磊石.血小板来源生长因子在活动性狼疮性肾炎肾小球病理改变的作用.中华内科杂志.1996; 35(9):601-5.
71. Troyer DA, Chandrasekar B, Barnes JL, Fernandes G. Calorie restriction decreases platelet-derived growth factor (PDGF)-A and thrombin receptor mRNA expression in autoimmune murine lupus nephritis. Clin Exp Immunol. 1997; 108(1):58-62.
72. Hintzen C, Quaiser S, Pap T, Heinrich PC, Hermanns HM. Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis. Arthritis Rheum. 2009; 60(7):1932-43.
73. Upadhyay A, Sharma G, Kivivuori S, Raye WS, Zabihi E, Carroll GJ, Jazayeri JA. Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. Cytokine. 2009; 46(3):332-8.
74.郭克泰. FcεR1信号传导途径与过敏性疾病的治疗.国外医学免疫学分册.2002;25(5):237-40.
75. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Kr?mer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 2008; 4(8):e1000166.
76. Sanak M, Potaczek DP, Sznajd J, Musia? J, Szczeklik A. Genetic associations of variants of the high affinity receptor for immunoglobulin E in Wegener's granulomatosis. Pol Arch Med Wewn. 2009; 119(3):170-4.
77.傅用增,来鲁华. SH2结构域:一个潜在的药靶.生命的化学.2008; 28(2):194-6.
78. Linghu H, Tsuda M. Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS .Oncogene. 2006; 25(25):3547-56.
79. Sonia P, Rodrigues. CrkI and CrkII function as key signaling integrators for migration and invasion of cancer cells.Molecular Cancer Research. 2005; 3(2):183-194.
80. Pfrepper KI, Marie-Cardine A, Simeoni L, Kuramitsu Y, Leo A, Spicka J, Hilgert I, Scherer J, Schraven B. Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein). Eur J Immunol. 2001; 31(6):1825-36.
81. Homsi J, Cubitt C, Daud A. The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets. 2007; 11(1):91-100.
82. Chen FW, Ioannou YA. Ribosomal proteins in cell proliferation and apoptosis. Int Rev Immunol. 1999; 18(5-6):429-48.
83. Houston IB, Kamath MB, Schweitzer BL, Chlon TM, DeKoter RP. Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality. Exp Hematol. 2007; 35(7):1056-68.
84.刘辉,姚咏明.细胞内炎症信号通路交汇作用研究进展.感染、炎症、修复. 2003;4(4):241-5.
85. Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol. 2007; 82(2):237-43.
86. Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2006; 7(4):225-35.
1. O'Shea JJ, Notarangelo LD, Johnston JA, Candotti F. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency. J Clin Immunol. 1997; 17(6):431-47.
2. Arbouzova NI, Zeidler MP. JAK/STAT signaling in Drosophila: insights intoconserved regulatory and cellular functions. Development. 2006; 133(14):2605-16.
3. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of negative regulators of signal transduction. J Leukoc Biol. 1998; 63(6):665-8.
4. Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell Res. 2006; 16(2):196-202.
5. Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. Bioessays. 1999; 21(1):47-52.
6. Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem Cells. 2001; 19(5):378-87.
7. Tan JC, Rabkin R. Suppressors of cytokine signaling in health and disease. Pediatr Nephrol. 2005; 20(5):567-75.
8. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T. Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997; 387(6636):924-9.
9. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997; 387(6636):921-4.
10. Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A, Yoshimura A. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood. 1997; 89(9):3148-54.
11. Kamura T, Sato S, Haque D, Liu L, Kaelin WG Jr, Conaway RC, Conaway JW. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 1998; 12(24):3872-81.
12. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K. Specific inhibition of Stat3 signal transduction by PIAS3.Science. 1997;278(5344):1803-5.
13. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 1998; 95(18):10626-31.
14. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996; 84(3):431-42.
15. Neubauer H, Cumano A, Müller M,Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998, 93:397-409.
16. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O’Shea JJ, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995, 377(6544):65-8.
17. Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, McCoy B, Bogdan C, Decker T, Brem G, Pfeffer K, Müller M. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000; 13(4):549-60.
18. Nishibori T, Tanabe Y, Su L, David M. Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med. 2004; 199(1):25-34.
19. Park C, Li S, Cha E, Schindler C: Immune response in Stat2 knockout mice. Immunity 2000; 13(6):795-804.
20. Matsukawa A, Takeda K, Kudo S, Maeda T, Kagayama M, Akira S. Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils. J Immunol. 2003; 171(11):6198-205.
21. Matsukawa A, Kudo S, Maeda T, Numata K, Watanabe H, Takeda K, Akira S, Ito T. Stat3 in resident macrophages as a repressor protein of inflammatory response. JImmunol. 2005; 175(5):3354-9.
22. O'Malley JT, Sehra S, Thieu VT, Yu Q, Chang HC, Stritesky GL, Nguyen ET, Mathur AN, Levy DE, Kaplan MH. Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology. 2009; 127(4):587-95.
23. Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Goldsmith MA. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol. 2003; 171(10):5042-50.
24. Santos SJ, Haslam SZ, Conrad SE. Estrogen and progesterone are critical regulators of Stat5a expression in the mouse mammary gland. Endocrinology. 2008; 149(1):329-38.
25. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996, 380(6575):630-3.
26. Takeda K, Kishimoto T, Akira S. STAT6:its role in interleukin 4-mediated biological functions. J Mol Med. 1997; 75(5):317-26.
27. J?nsen A, Bengtsson AA, Nived O, Truedsson L, Sturfelt G. Gene-environment interactions in the aetiology of systemic lupus erythematosus. Autoimmunity. 2007; 40(8):613-7.
28. Kyttaris VC, Krishnan S, Tsokos GC. Systems biology in systemic lupus erythematosus: integrating genes, biology and immune function. Autoimmunity. 2006; 39(8):705-9.
29. Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res. 2010; 155(3):109-17.
30. Louren?o EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med. 2009; 9(3):242-54.
31.陶金辉,李向培,厉小梅,汪国生,钱龙,王玮. IFN-γ在系统性红斑狼疮发病中的作用和临床意义.疾病控制杂志2005; 9(3):278-80.
32. Peng SL. Transcription factors in autoimmune diseases. Front Biosci. 2008; 13:4218-40.
33. R?nnblom L, Alm GV, Eloranta ML. Type I interferon and lupus. Curr Opin Rheumatol. 2009; 21(5):471-7.
34. Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol. 2004; 16(6):801-7.
35. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5.
36. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003; 197(6):711-23.
37. Suh CH, Kim HA. Cytokines and their receptors as biomarkers of systemic lupus erythematosus. Expert Rev Mol Diagn. 2008; 8(2):189-98.
38. Lee PY, Reeves WH. Type I interferon as a target of treatment in SLE. Endocr Metab Immune Disord Drug Targets. 2006; 6(4):323-30.
39. Karonitsch T, Feierl E, Steiner CW, Dalwigk K, Korb A, Binder N, Rapp A, Steiner G, Scheinecker C, Smolen J, Aringer M. Activation of the interferon-gamma signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells. Arthritis Rheum. 2009; 60(5):1463-71.
40. Martinez-Lostao L, Ordi-Ros J, Balada E, Segarra-Medrano A, Majó-Masferrer J, Labrador-Horrillo M, Vilardell-Tarrés M. Activation of the signal transducer and activator of transcription-1 in diffuse proliferative lupus nephritis. Lupus. 2007; 16(7):483-8.
41. Dong J, Wang QX, Zhou CY, Ma XF, Zhang YC. Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus. 2007; 16(2):101-9.
42. Wang L, Tassiulas I, Park-Min KH, Reid AC, Gil-Henn H, Schlessinger J, Baron R, Zhang JJ, Ivashkiv LB. 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol. 2008; 9(2):186-93.
43. Sharabi A, Sthoeger ZM, Mahlab K, Lapter S, Zinger H, Mozes E. A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZB x NZW) F1 mice. Clin Immunol. 2009; 133(1):61-8.
44. Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, Kim SH, Park HS, Suh CH.Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol. 2007; 27(5):461-6.
45. Sabry A, Sheashaa H, El-Husseini A, Mahmoud K, Eldahshan KF, George SK, Abdel-Khalek E, El-Shafey EM, Abo-Zenah H. Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine. 2006; 35(3-4):148-53.
46. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007; 40(1):1-8.
47. Hale MB, Krutzik PO, Samra SS, Crane JM, Nolan GP. Stage dependent aberrant regulation of cytokine-STAT signaling in murine systemic lupus erythematosus. PLoS One. 2009; 4(8):e6756.
48. Pflegerl P, Vesely P, Hantusch B, Schlederer M, Zenz R, Janig E, Steiner G, Meixner A, Petzelbauer P, Wolf P, Soleiman A, Egger G, Moriggl R, Kishimoto T, Wagner EF, Kenner L. Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling. Proc Natl Acad Sci U S A. 2009; 106(48):20423-8.
49. Pramanik R, J?rgensen TN, Xin H, Kotzin BL, Choubey D. Interleukin-6 inducesexpression of Ifi202, an interferon-inducible candidate gene for lupus susceptibility. J Biol Chem. 2004; 279(16):16121-7.
50. Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology. 2006; 119(3):296-305.
51. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004; 202:139-56.
52. Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, Jacob CO. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol. 2003; 170(9):4818-25.
53. Li Z, Li Y, Huang L, Xu H, Yu X, Ye R. Expression of interleukin-12 and its signaling molecules in peripheral blood mononuclear cells in systemic lupus erythematosus patients. Chin Med J (Engl). 2002; 115(6):846-50.
54. Xu Z, Duan B, Croker BP, Morel L. STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol. 2006; 120(2):189-98.
55. Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol. 2009; 182(1):34-8.
56. Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, Ye DQ. A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol. 2010. [Epub ahead of print]
57. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, Gao F, Zhang PL, Guo Q, Li B,Gao M, Xiao FL, Quan C, Zhang C, Zhang Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009; 41(11):1234-7.
58. Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. Arthritis Res Ther. 2008; 10(5):R113.
59. Suarez-Gestal M, Calaza M, Endreffy E, Pullmann R, Ordi-Ros J, Domenico Sebastiani G, Ruzickova S, Jose Santos M, Papasteriades C, Marchini M, Skopouli FN, Suarez A, Blanco FJ, D'Alfonso S, Bijl M, Carreira P, Witte T, Migliaresi S, Gomez-Reino JJ, Gonzalez A; European Consortium of SLE DNA Collections. Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res Ther. 2009; 11(3):R69.
60. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007; 357(10):977-86.
61. Jacob CO, Zang S, Li L, Ciobanu V, Quismorio F, Mizutani A, Satoh M, Koss M. Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol. 2003; 171(3):1564-71.
62. Nguyen H, Hiscott J, Pitha PM. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 1997; 8(4):293-312.
63. Ozato K, Tailor P, Kubota T. The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem. 2007; 282(28):20065-9.
64. Savitsky D, Tamura T, Yanai H, Taniguchi T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother. 2010; 59(4):489-510.
65. Lohoff M, Gessner A, Bogdan C, R?llinghoff M. Experimental murine leishmaniasis and the Th1/Th2 cell concept. Tokai J Exp Clin Med. 1998; 23(6):347-50.
66.钱捷,沈南,郭桂梅,万年红,林燕,黄新芳,吴慧,陈顺乐.系统性红斑狼疮患者干扰素调节因子IRF1 IRF4 IRF8基因表达的研究.中华风湿病学杂志,2006;10(9):513-6.
67. Reilly CM, Olgun S, Goodwin D, Gogal RM Jr, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS. Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006; 36(5):1296-308.
68. Salloum R, Franek BS, Kariuki SN, Rhee L, Mikolaitis RA, Jolly M, Utset TO, Niewold TB. Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients. Arthritis Rheum. 2010; 62(2):553-61.
69. Akahoshi M, Nakashima H, Sadanaga A, Miyake K, Obara K, Tamari M, Hirota T, Matsuda A, Shirakawa T. Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus. Lupus. 2008; 17(6):568-74.
70. Sánchez E, González-Gay MA, Callejas-Rubio JL, Ortego-Centeno N, Sabio JM, Jiménez-Alonso J, MicóL, Suarez A, Gutierrez C, de Ramón E, Camps M, Garcia-Portales R, Tolosa C, López-Nevot MA, Sánchez-Román J, Hernández FJ, González-Escribano MF, Martín J. No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus. Lupus. 2009; 18(3):230-4.
71. Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK.Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008; 58(8):2481-7.
72. Lee YH, Song GG. Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis. Rheumatol Int. 2009; 29(10):1137-42.
73. Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Leung AM, Li XP, Avihingsanon Y, Wong CM, Lee TL, Ho MH, Lee PP, Chang YK, Li PH, Li RJ, Zhang L, Wong WH, Ng IO, Lau CS, Sham PC, Lau YL; Asian Lupus Genetics Consortium. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010; 6(2):e1000841.
74. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G, Syv?nen AC, R?nnblom L, Barnes BJ. Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2010; 62(2):562-73.
75. Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, Merrill JT, James JA, Frank SG, Reams E, Brown EE, Gibson AW, Marion MC, Langefeld CD, Li QZ, Karp DR, Wakeland EK, Petri M, Ramsey-Goldman R, Reveille JD, ViláLM, Alarcón GS, Kimberly RP, Harley JB, Edberg JC. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun. 2008; 9(3):187-94.
76. Sigurdsson S, Nordmark G, G?ring HH, Lindroos K, Wiman AC, Sturfelt G, J?nsen A, Rantap??-Dahlqvist S, M?ller B, Kere J, Koskenmies S, Widén E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, R?nnblom L, Syv?nen AC. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes areassociated with systemic lupus erythematosus. Am J Hum Genet. 2005; 76(3):528-37.
77. Kyogoku C, Morinobu A, Nishimura K, Sugiyama D, Hashimoto H, Tokano Y, Mimori T, Terao C, Matsuda F, Kuno T, Kumagai S. Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population. Mod Rheumatol. 2009; 19(4):401-6.
78. Hellquist A, J?rvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D'Amato M, Saarialho-Kere U, Kere J. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009; 36(8):1631-8.
79. Suarez-Gestal M, Calaza M, Gonzalez A. Lack of interaction between systemic lupus erythematosus-associated polymorphisms in TYK2 and IRF5. J Rheumatol. 2010; 37(3): 676-7.
80. Firestein GS. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol. 2005; 11(3 Suppl):S39-44.
81. Okamoto H, Hoshi D, Kiire A, Yamanaka H, Kamatani N. Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets. 2008; 7(1):53-66.
82. Taylor PC. Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. Curr Pharm Des. 2003; 9(14):1095-106.
83. Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol. 2005; 32(9):1650-3.
84. Yokota A, Narazaki M, Shima Y, Murata N, Tanaka T, Suemura M, Yoshizaki K, Fujiwara H, Tsuyuguchi I, Kishimoto T. Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells. J Rheumatol. 2001; 28(9):1952-9.
85. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJ, Kraan MC, Fero M, Tak PP, Huizinga TW, Pieterman E, Breedveld FC, AlizadehAA, Verweij CL. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003; 4 8(8):2132-45.
86. Isom?ki P, Alan?r? T, Isohanni P, Lagerstedt A, Korpela M, Moilanen T, Visakorpi T, Silvennoinen O. The expression of SOCS is altered in rheumatoid arthritis. Rheumatology (Oxford). 2007; 46(10):1538-46.
87. de Hooge AS, van de Loo FA, Koenders MI, Bennink MB, Arntz OJ, Kolbe T, van den Berg WB. Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice. Arthritis Rheum. 2004; 50(6):2014-23.
88. Wong PK, Egan PJ, Croker BA, O'Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest. 2006; 116(6):1571-81.
89. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJ, Kraan MC, Fero M, Tak PP, Huizinga TW, Pieterman E, Breedveld FC, Alizadeh AA, Verweij CL. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003; 48(8):2132-45.
90. Wang F, Sengupta TK, Zhong Z, Ivashkiv LB. Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J Exp Med. 1995; 182(6):1825-31.
91.杨馨,李继书,杨慎峭,张新星,张天生,周海燕,刘旭光.艾灸对实验性类风湿性关节炎家兔滑膜细胞JAK-STAT信号通路影响的研究.针刺研究. 2007; 32(4):75-82.
92. Hildner KM, Schirmacher P, Atreya I, Dittmayer M, Bartsch B, Galle PR, Wirtz S,Neurath MF. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J Immunol. 2007; 178(6):3427-36.
93. Finnegan A, Grusby MJ, Kaplan CD, O'Neill SK, Eibel H, Koreny T, Czipri M, Mikecz K, Zhang J. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol. 2002; 169(6):3345-52.
94. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest. 2001; 108(5):739-47.
95. Boyton RJ, Davies S, Marden C, Fantino C, Reynolds C, Portugal K, Dewchand H, Altmann DM. Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread. Int Immunol. 2005; 17(9):1157-65.
96. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2010; 30(5):661-6.
97. Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MA, Balsa A, Pascual-Salcedo D, Fernández-Gutierrez B, González-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcón-Riquelme M, Martín J. Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum. 2008; 58(7):1974-80.
98. Zervou MI, Sidiropoulos P, Petraki E, Vazgiourakis V, Krasoudaki E, Raptopoulou A, Kritikos H, Choustoulaki E, Boumpas DT, Goulielmos GN. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol. 2008; 69(9):567-71.
99. Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, Nakamura Y, Toyama Y, Mochizuki T, Tsukahara S, Kawaguchi Y, Terai C, Hara M, Tomatsu T, Yamanaka H, Horiuchi T, Tao K, Yasutomo K, Hamada D, Yasui N, Inoue H, Itakura M, Okamoto H, Kamatani N, Momohara S. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum. 2008; 58(7):1940-6.
100. Martínez A, VaradéJ, Márquez A, Cénit MC, Espino L, Perdigones N, Santiago JL, Fernández-Arquero M, de la Calle H, Arroyo R, Mendoza JL, Fernández-Gutiérrez B, de la Concha EG, Urcelay E. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum. 2008; 58(9):2598-602.
101.Finnegan A, Grusby MJ, Kaplan CD, O'Neill SK, Eibel H, Koreny T, Czipri M, Mikecz K, Zhang J. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol. 2002 Sep 15; 169(6):3345-52.
102.Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009; 94(9):3171-82.
103.Peng SL. Transcription factors in autoimmune diseases. Front Biosci. 2008; 13:4218-40.
104.Litherland SA, Grebe KM, Belkin NS, Paek E, Elf J, Atkinson M, Morel L, Clare-Salzler MJ, McDuffie M. Nonobese diabetic mouse congenic analysis reveals chromosome 11 locus contributing to diabetes susceptibility, macrophage STAT5 dysfunction, and granulocyte-macrophage colony-stimulating factor overproduction. J Immunol. 2005; 175 (7):4561-5.
105.Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, McDuffie M, Nadler JL. Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun. 2004; 22(3):191-200.
106.Homann D, Holz A, Bot A, Coon B, Wolfe T, Petersen J, Dyrberg TP, Grusby MJ, von Herrath MG. Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. Immunity. 1999; 11(4):463-72.
107.Zheng SJ, Lamhamedi-Cherradi SE, Wang P, Xu L, Chen YH. Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function. Diabetes. 2005; 54(5):1423-8.
108.Kim S, Kim HS, Chung KW, Oh SH, Yun JW, Im SH, Lee MK, Kim KW, Lee MS. Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice. Diabetes. 2007; 56(10):2561-8.
109.Chong MM, Thomas HE, Kay TW. Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem. 2002; 277(31):27945-52.
110.Mori H, Shichita T, Yu Q, Yoshida R, Hashimoto M, Okamoto F, Torisu T, Nakaya M, Kobayashi T, Takaesu G, Yoshimura A. Suppression of SOCS3 expression in the pancreatic beta-cell leads to resistance to type 1 diabetes. Biochem Biophys Res Commun. 2007; 359(4):952-8.
111.Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab. 2006; 17(9):365-71.
112.Lee HS, Park H, Yang S, Kim D, Park Y.STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci. 2008; 1150:93-8.
113.Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009; 361(21):2066-78.
114.Mudter J, Neurath MF. The role of signal transducers and activators of transcription in inflammatory bowel diseases. Inflamm Bowel Dis. 2003; 9(5):332-7.
115.Mudter J, Weigmann B, Bartsch B, Kiesslich R, Strand D, Galle PR, Lehr HA,Schmidt J, Neurath MF. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol. 2005; 100(1):64-72.
116.Pang YH, Zheng CQ, Yang XZ, Zhang WJ. Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cell Immunol. 2007; 248(2):115-20.
117.Parrello T, Monteleone G, Cucchiara S, Monteleone I, Sebkova L, Doldo P, Luzza F, Pallone F. Up-regulation of the IL-12 receptor beta 2 chain in Crohn's disease. J Immunol. 2000; 165(12):7234-9.
118.Musso A, Dentelli P, Carlino A, Chiusa L, Repici A, Sturm A, Fiocchi C, Rizzetto M, Pegoraro L, Sategna-Guidetti C, Brizzi MF. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis. 2005; 11(2):91-8.
119.Han X, Sosnowska D, Bonkowski EL, Denson LA. Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Gastroenterology. 2005; 129(1):185-203.
120.Mitsuyama K, Matsumoto S, Masuda J, Yamasakii H, Kuwaki K, Takedatsu H, Sata M. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res. 2007; 27(6A):3749-56.
121.Ferguson LR, Han DY, Fraser AG, Huebner C, Lam WJ, Morgan AR, Duan H, Karunasinghe N. Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population. Mutat Res. 2010. [Epub ahead of print]
122.Cénit MC, Alcina A, Márquez A, Mendoza JL, Díaz-Rubio M, de Las Heras V, Izquierdo G, Arroyo R, Fernández O, de la Concha EG, Matesanz F, Urcelay E.STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun. 2010 [Epub ahead of print]
123.Sato K, Shiota M, Fukuda S, Iwamoto E, Machida H, Inamine T, Kondo S, Yanagihara K, Isomoto H, Mizuta Y, Kohno S, Tsukamoto K. Strong evidence of a combination polymorphism of the tyrosine kinase 2 gene and the signal transducer and activator of transcription 3 gene as a DNA-based biomarker for susceptibility to Crohn's disease in the Japanese population. J Clin Immunol. 2009; 29(6):815-25.
124.Diaz-Gallo LM, Palomino-Morales RJ, Gómez-García M, Carde?a C, Rodrigo L, Nieto A, Alcain G, Cueto I, López-Nevot MA, Martin J. STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: A replication study. Hum Immunol. 2010. [Epub ahead of print]
125.Cannella B, Raine CS. Multiple sclerosis: cytokine receptors on oligodendrocytes predict innate regulation. Ann Neurol. 2004; 55(1):46-57.
126.Land KJ, Moll JS, Kaplan MH, Seetharamaiah GS. Signal transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in Graves' hyperthyroidism. Endocrinology. 2004; 145(8):3724-30.
127.Jackson M, Howie SE, Weller R, Sabin E, Hunter JA, McKenzie RC. Psoriatic keratinocytes show reduced IRF-1 and STAT-1alpha activation in response to gamma-IFN. FASEB J. 1999; 13(3):495-502.
128.Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J.Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. 2005; 11(1):43-9.
129.Tayal V, Kalra BS.Cytokines and anti-cytokines as therapeutics--an update. Eur J Pharmacol. 2008; 579(1-3):1-12.
130.Jo D, Liu D, Yao S, Collins RD, Hawiger J.Intracellular protein therapy withSOCS3 inhibits inflammation and apoptosis. Nat Med. 2005; 11(8):892-8.
131.Yamamoto M, Nishimoto N, Davydova J, Kishimoto T, Curiel DT. Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells. Cancer Gene Ther. 2006; 13(2):194-202.
132.王克明,王彬. JAK/STAT通路阻断剂AG490的研究现状.现代泌尿外科杂志. 2003;8(1):57-9.
133.Caceres-Cortes JR. A potent anti-carcinoma and anti-acute myeloblastic leukemia agent, AG490. Anticancer Agents Med Chem. 2008; 8(7):717-22.
134.S?emann MD, B?hmig GA, Osterreicher CH, Staffler G, Diakos C, Krieger PM, H?rl WH, Stockinger H, Zlabinger GJ.Suppression of primary T-cell responses and induction of alloantigen-specific hyporesponsiveness in vitro by the Janus kinase inhibitor tyrphostin AG490. Transplantation. 2000; 70(8):1215-25.
135.高薇,杨娉婷,沈晖,鲁静,肖卫国,赵丽娟.阻断JAK2STAT信号通路对大鼠类风湿关节炎治疗作用的实验研究.中国实用内科杂志. 2007;27(11):872-5.
136.Changelian PS, Moshinsky D, Kuhn CF, Flanagan ME, Munchhof MJ, Harris TM, Whipple DA, Doty JL, Sun J, Kent CR, Magnuson KS, Perregaux DG, Sawyer PS, Kudlacz EM. The specificity of JAK3 kinase inhibitors. Blood. 2008; 111(4):2155-7.
2. Louren?o EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med. 2009; 9(3):242-54.
3. Meyer O. Interferons and autoimmune disorders. Joint Bone Spine. 2009; 76(5):464-73.
4. Dall’era MC, Cardarelli PM, Preston BT, Witte A, Davis JC Jr. Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis 2005; 64(12): 1692-97.
5. Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, Tsao BP. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006; 54(9):2951-62.
6.吴元胜,范瑞强,陈达灿,禤国维.基因芯片技术分析系统性红斑狼疮患者外周血白细胞基因表达谱的初步研究.第一军医大学学报. 2005; 25(8):929-34.
7. Nicoletti F, Di Marco R, Zaccone P, Xiang M, Magro G, Grasso S, Morrone S, Santoni A, Shoenfeld Y, Garotta G, Meroni P. Dichotomic effects of IFN-gamma on the development of systemic lupus erythematosus-like syndrome in MRL-lpr / lpr mice. Eur J Immunol. 2000; 30(2):438-47.
8. Arbouzova NI, Zeidler MP. JAK/STAT signaling in Drosophila: insights into conserved regulatory and cellular functions. Development. 2006; 133(14):2605-16.
9. O'Shea JJ, Notarangelo LD, Johnston JA, Candotti F. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency. J Clin Immunol. 1997; 17(6):431-47.
10.张树民. JAK-STAT和免疫系统的关系.国外医学免疫学分册. 1999; 22(5):294-7.
11. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of negative regulators of signal transduction. J Leukoc Biol. 1998; 63(6):665-8.
12. Harley JB, Kelly JA, Kaufman KM. Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol. 2006; 28(2):119-30.
13. Rhodes B, Vyse TJ. The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology (Oxford). 2008; 7(11):1603-11.
14. Graham RR, Hom G, Ortmann W, Behrens TW. Review of recent genome-wide association scans in lupus. J Intern Med. 2009; 265(6):680-8.
15. Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res. 2010; 155(3):109-17.
16.董静,蒋艳霞,刘爱国,王少春,杨清锐,张源潮. MRL/lpr小鼠肾组织JAK/STAT信号转导途径的表达和雷帕霉素对其表达的影响.中华微生物学和免疫学杂志. 2007; 27(6):490-4.
17. Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, Jacob CO. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. JImmunol. 2003; 170(9):4818-25.
18. Valencia-Pacheco G, Layseca-Espinosa E, Ni?o-Moreno P, Portales-Pérez DP, Baranda L, Rosenstein Y, Abud-Mendoza C, González-Amaro R. Expression and function of IL-10R in mononuclear cells from patients with systemic lupus erythematosus. Scand J Rheumatol. 2006; 35(5):368-78.
19. Hellquist A, J?rvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D'Amato M, Saarialho-Kere U, Kere J. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009; 36(8):1631-8.
20. Sigurdsson S, Nordmark G, G?ring HH, Lindroos K, Wiman AC, Sturfelt G, J?nsen A, Rantap??-Dahlqvist S, M?ller B, Kere J, Koskenmies S, Widén E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, R?nnblom L, Syv?nen AC. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet. 2005; 76(3):528-37.
21. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007; 40(1):1-8.
22.黎莉,陈顺乐,沈南,鲍春德,钱捷,叶萍,顾越英,王元.系统性红斑狼疮初发患者Th细胞异常分化相关分子基因表达研究.中华风湿病学杂志. 2003; 7(3):133-8.
23. Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, Ye DQ. A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol. 2010. [Epub ahead of print]
24. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, KastnerDL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007; 357(10):977-86.
25. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, Gao F, Zhang PL, Guo Q, Li B, Gao M, Xiao FL, Quan C, Zhang C, Zhang Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009; 41(11):1234-7.
26. Neubauer H, Cumano A, Müller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998, 93(3):397-409.
27.杨馨,李继书,杨慎峭,张新星,张天生,周海燕,刘旭光.艾灸对实验性类风湿性关节炎家兔滑膜细胞JAK-STAT信号通路影响的研究.针刺研究. 2007; 32(4):75-82.
28. Bright JJ, Du C, Sriram S. Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 1999; 162(10):6255-62.
29.高薇,杨娉婷,沈晖,鲁静,肖卫国,赵丽娟.阻断JAK2-STAT信号通路对大鼠类风湿关节炎治疗作用的实验研究.中国实用内科杂志. 2007;27(11):872-5.
30. Croker BA, Kiu H, Nicholson SE. SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol. 2008; 19(4):414-22.
31. Song MM, Shuai K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferativeactivities. J Biol Chem. 1998; 273(52):35056-62.
32. Dong J, Wang QX, Zhou CY, Ma XF, Zhang YC. Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus. 2007; 16(2):101-9.
33. Tsao JT, Kuo CC, Lin SC. The analysis of CIS, SOCS1, SOSC2 and SOCS3 transcript levels in peripheral blood mononuclear cells of systemic lupus erythematosus and rheumatoid arthritis patients. Clin Exp Med. 2008; 8(4):179-85.
34. Losana G, Rigamonti L, Borghi I, Assenzio B, Ariotti S, Jouanguy E, Altare F, Forni G, Casanova JL, Novelli F. Requirement for both IL-12 and IFN-gamma signaling pathways in optimal IFN-gamma production by human T cells. Eur J Immunol. 2002; 32(3):693-700.
35. Haas C, Ryffel B, Le Hir M. IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW)F1 mice. J Immunol. 1998; 160(8):3713-8.
36. Tanaka Y, Nakashima H, Hisano C, Kohsaka T, Nemoto Y, Niiro H, Otsuka T, Otsuka T, Imamura T, Niho Y. Association of the interferon-gamma receptor variant (Val14Met) with systemic lupus erythematosus. Immunogenetics. 1999; 49(4):266-71.
37. Xu Y, Chen ZQ, Li YM, Gong JQ, Li AS, Chen M, Liu J. Correlation between some Th1 and Th2 cytokine receptor gene polymorphisms and systemic lupus erythematosus in Chinese patients. Int J Dermatol. 2007; 46(11):1129-35.
38. Ozmen L, Roman D, Fountoulakis M, Schmid G, Ryffel B, Garotta G. Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis. Eur J Immunol. 1995; 25(1):6-12.
39. Lawson BR, Prud'homme GJ, Chang Y, Gardner HA, Kuan J, Kono DH, Theofilopoulos AN. Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc. J Clin Invest. 2000; 106(2):207-15.
40. Randhawa SR, Chahine BG, Lowery-Nordberg M, Cotelingam JD, Casillas AM. Underexpression and overexpression of Fas and Fas ligand: a double-edged sword. Ann Allergy Asthma Immunol. 2010; 104(4):286-92.
41. Battle TE, Frank DA.The role of STATs in apoptosis. Curr Mol Med. 2002; 2(4):381-92.
42. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS. 2006; 114(9):619-25.
43. Desrivières S, Kunz C, Barash I, Vafaizadeh V, Borghouts C, Groner B.The biological functions of the versatile transcription factors STAT3 and STAT5 and new strategies for their targeted inhibition. J Mammary Gland Biol Neoplasia. 2006; 11(1):75-87.
44. Suk K, Kim S, Kim YH, Kim KA, Chang I, Yagita H, Shong M, Lee MS. IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol. 2001; 166(7):4481-9.
45. Cousens LP, Goulette FA, Darnowski JW. JAK-mediated signaling inhibits Fas ligand-induced apoptosis independent of de novo protein synthesis. J Immunol. 2005; 174(1):320-7.
46. Li LH, Li WX, Wu O, Zhang GQ, Pan HF, Li XP, Xu JH, Dai H, Ye DQ. Fas expression on peripheral blood lymphocytes in systemic lupus erythematosus: relation to the organ damage and lymphocytes apoptosis. Mol Biol Rep. 2009; 36(8):2047-52.
47. Araste JM, Sarvestani EK, Aflaki E, Amirghofran Z. Fas gene polymorphisms in systemic lupus erythematosus and serum levels of some apoptosis-related molecules. Immunol Invest. 2010; 39(1):27-38.
48.叶霜,沈南,顾越英,陈顺乐,韩光明,冯修高,冯学兵,陈兴国,华晶,黄文群,王元,鲍春德.系统性红斑狼疮的基因表达谱及其免疫调控通路的研究.中华风湿病学杂志. 2002; 6(6):411-16.
49. Feng X, Wu H, Grossman JM, Hanvivadhanakul P, FitzGerald JD, Park GS, Dong X, Chen W, Kim MH, Weng HH, Furst DE, Gorn A, McMahon M, Taylor M, Brahn E, Hahn BH, Tsao BP. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006; 54(9):2951-62.
50. Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, Peterson LF, Shuai K, Zhang DE. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev. 2003; 17(4):455-60.
51. Brand S, Zitzmann K, Dambacher J, Beigel F, Olszak T, Vlotides G, Eichhorst ST, G?ke B, Diepolder H, Auernhammer CJ. SOCS-1 inhibits expression of the antiviral proteins 2',5'-OAS and MxA induced by the novel interferon-lambdas IL-28A and IL-29. Biochem Biophys Res Commun. 2005; 331(2):543-8.
52. Preble OT, Rothko K, Klippel JH, Friedman RM, Johnston MI. Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon. J Exp Med. 1983; 157(6):2140-6.
53. Jeon YJ, Yoo HM, Chung CH. ISG15 and immune diseases. Biochim Biophys Acta. 2010; 1802(5):485-96.
54. Ozato K, Tailor P, Kubota T. The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem. 2007; 282(28):20065-9.
55.钱捷,沈南,郭桂梅,万年红,林燕,黄新芳,吴慧,陈顺乐.系统性红斑狼疮患者干扰素调节因子IRF1 IRF4 IRF8基因表达的研究.中华风湿病学杂志,2006;10(9):513-6.
56. Reilly CM, Olgun S, Goodwin D, Gogal RM Jr, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS. Interferon regulatory factor-1 gene deletion decreasesglomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006; 36(5):1296-308.
57. Akahoshi M, Nakashima H, Sadanaga A, Miyake K, Obara K, Tamari M, Hirota T, Matsuda A, Shirakawa T. Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus. Lupus. 2008; 17(6):568-74.
58. Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008; 58(8):2481-7.
59. Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, Merrill JT, James JA, Frank SG, Reams E, Brown EE, Gibson AW, Marion MC, Langefeld CD, Li QZ, Karp DR, Wakeland EK, Petri M, Ramsey-Goldman R, Reveille JD, ViláLM, Alarcón GS, Kimberly RP, Harley JB, Edberg JC. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun. 2008; 9(3):187-94.
60. Tsuno T, Mejido J, Zhao T, Schmeisser H, Morrow A, Zoon KC. IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha. J Immunother. 2009;32(8):803-16.
61. Coqueret O, Gascan H. Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1. J Biol Chem. 2000; 275(25):18794-800.
62. Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, Hamilton SR, Amin HM. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005; 167(4):969-80.
63. Tanaka M, Miyajima A. Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol. 2003; 149:39-52.
64. Liu J, Hadjokas N, Mosley B, Estrov Z, Spence MJ, Vestal RE. Oncostatin M-specific receptor expression and function in regulating cell proliferation ofnormal and malignant mammary epithelial cells. Cytokine. 1998; 10(4):295-302.
65. Radtke S, Hermanns HM, Haan C, Schmitz-Van De Leur H, Gascan H, Heinrich PC, Behrmann I. Novel role of Janus kinase 1 in the regulation of oncostatin M receptor surface expression. J Biol Chem.2002; 277 (13):11297-305.
66. Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol. 1996; 16(4):1759-69.
67. Floege J, van Roeyen C, Boor P, Ostendorf T. The role of PDGF-D in mesangioproliferative glomerulonephritis. Contrib Nephrol. 2007; 157:153-8.
68. Hirai T, Masaki T, Kuratsune M, Yorioka N, Kohno N. PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell proliferation involving STAT3 activation. Clin Exp Immunol. 2006; 144(2):353-61.
69.陆青,沈南,陈顺乐,倪旭鸣. NZB/W狼疮鼠体外IFN-α信号调控网络研究.现代免疫学.2008; 28(4):305-11.
70.郑丰,刘志红,周虹,张京红,钱斌,唐政,陈慧平,黎磊石.血小板来源生长因子在活动性狼疮性肾炎肾小球病理改变的作用.中华内科杂志.1996; 35(9):601-5.
71. Troyer DA, Chandrasekar B, Barnes JL, Fernandes G. Calorie restriction decreases platelet-derived growth factor (PDGF)-A and thrombin receptor mRNA expression in autoimmune murine lupus nephritis. Clin Exp Immunol. 1997; 108(1):58-62.
72. Hintzen C, Quaiser S, Pap T, Heinrich PC, Hermanns HM. Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis. Arthritis Rheum. 2009; 60(7):1932-43.
73. Upadhyay A, Sharma G, Kivivuori S, Raye WS, Zabihi E, Carroll GJ, Jazayeri JA. Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. Cytokine. 2009; 46(3):332-8.
74.郭克泰. FcεR1信号传导途径与过敏性疾病的治疗.国外医学免疫学分册.2002;25(5):237-40.
75. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Kr?mer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 2008; 4(8):e1000166.
76. Sanak M, Potaczek DP, Sznajd J, Musia? J, Szczeklik A. Genetic associations of variants of the high affinity receptor for immunoglobulin E in Wegener's granulomatosis. Pol Arch Med Wewn. 2009; 119(3):170-4.
77.傅用增,来鲁华. SH2结构域:一个潜在的药靶.生命的化学.2008; 28(2):194-6.
78. Linghu H, Tsuda M. Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS .Oncogene. 2006; 25(25):3547-56.
79. Sonia P, Rodrigues. CrkI and CrkII function as key signaling integrators for migration and invasion of cancer cells.Molecular Cancer Research. 2005; 3(2):183-194.
80. Pfrepper KI, Marie-Cardine A, Simeoni L, Kuramitsu Y, Leo A, Spicka J, Hilgert I, Scherer J, Schraven B. Structural and functional dissection of the cytoplasmic domain of the transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor protein). Eur J Immunol. 2001; 31(6):1825-36.
81. Homsi J, Cubitt C, Daud A. The Src signaling pathway: a potential target in melanoma and other malignancies. Expert Opin Ther Targets. 2007; 11(1):91-100.
82. Chen FW, Ioannou YA. Ribosomal proteins in cell proliferation and apoptosis. Int Rev Immunol. 1999; 18(5-6):429-48.
83. Houston IB, Kamath MB, Schweitzer BL, Chlon TM, DeKoter RP. Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality. Exp Hematol. 2007; 35(7):1056-68.
84.刘辉,姚咏明.细胞内炎症信号通路交汇作用研究进展.感染、炎症、修复. 2003;4(4):241-5.
85. Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol. 2007; 82(2):237-43.
86. Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2006; 7(4):225-35.
1. O'Shea JJ, Notarangelo LD, Johnston JA, Candotti F. Advances in the understanding of cytokine signal transduction: the role of Jaks and STATs in immunoregulation and the pathogenesis of immunodeficiency. J Clin Immunol. 1997; 17(6):431-47.
2. Arbouzova NI, Zeidler MP. JAK/STAT signaling in Drosophila: insights intoconserved regulatory and cellular functions. Development. 2006; 133(14):2605-16.
3. Nicholson SE, Hilton DJ. The SOCS proteins: a new family of negative regulators of signal transduction. J Leukoc Biol. 1998; 63(6):665-8.
4. Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell Res. 2006; 16(2):196-202.
5. Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway. Bioessays. 1999; 21(1):47-52.
6. Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem Cells. 2001; 19(5):378-87.
7. Tan JC, Rabkin R. Suppressors of cytokine signaling in health and disease. Pediatr Nephrol. 2005; 20(5):567-75.
8. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akira S, Kishimoto T. Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997; 387(6636):924-9.
9. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997; 387(6636):921-4.
10. Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A, Yoshimura A. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood. 1997; 89(9):3148-54.
11. Kamura T, Sato S, Haque D, Liu L, Kaelin WG Jr, Conaway RC, Conaway JW. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 1998; 12(24):3872-81.
12. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K. Specific inhibition of Stat3 signal transduction by PIAS3.Science. 1997;278(5344):1803-5.
13. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 1998; 95(18):10626-31.
14. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996; 84(3):431-42.
15. Neubauer H, Cumano A, Müller M,Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998, 93:397-409.
16. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O’Shea JJ, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995, 377(6544):65-8.
17. Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, McCoy B, Bogdan C, Decker T, Brem G, Pfeffer K, Müller M. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000; 13(4):549-60.
18. Nishibori T, Tanabe Y, Su L, David M. Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med. 2004; 199(1):25-34.
19. Park C, Li S, Cha E, Schindler C: Immune response in Stat2 knockout mice. Immunity 2000; 13(6):795-804.
20. Matsukawa A, Takeda K, Kudo S, Maeda T, Kagayama M, Akira S. Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils. J Immunol. 2003; 171(11):6198-205.
21. Matsukawa A, Kudo S, Maeda T, Numata K, Watanabe H, Takeda K, Akira S, Ito T. Stat3 in resident macrophages as a repressor protein of inflammatory response. JImmunol. 2005; 175(5):3354-9.
22. O'Malley JT, Sehra S, Thieu VT, Yu Q, Chang HC, Stritesky GL, Nguyen ET, Mathur AN, Levy DE, Kaplan MH. Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology. 2009; 127(4):587-95.
23. Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Goldsmith MA. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J Immunol. 2003; 171(10):5042-50.
24. Santos SJ, Haslam SZ, Conrad SE. Estrogen and progesterone are critical regulators of Stat5a expression in the mouse mammary gland. Endocrinology. 2008; 149(1):329-38.
25. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996, 380(6575):630-3.
26. Takeda K, Kishimoto T, Akira S. STAT6:its role in interleukin 4-mediated biological functions. J Mol Med. 1997; 75(5):317-26.
27. J?nsen A, Bengtsson AA, Nived O, Truedsson L, Sturfelt G. Gene-environment interactions in the aetiology of systemic lupus erythematosus. Autoimmunity. 2007; 40(8):613-7.
28. Kyttaris VC, Krishnan S, Tsokos GC. Systems biology in systemic lupus erythematosus: integrating genes, biology and immune function. Autoimmunity. 2006; 39(8):705-9.
29. Kariuki SN, Niewold TB. Genetic regulation of serum cytokines in systemic lupus erythematosus. Transl Res. 2010; 155(3):109-17.
30. Louren?o EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med. 2009; 9(3):242-54.
31.陶金辉,李向培,厉小梅,汪国生,钱龙,王玮. IFN-γ在系统性红斑狼疮发病中的作用和临床意义.疾病控制杂志2005; 9(3):278-80.
32. Peng SL. Transcription factors in autoimmune diseases. Front Biosci. 2008; 13:4218-40.
33. R?nnblom L, Alm GV, Eloranta ML. Type I interferon and lupus. Curr Opin Rheumatol. 2009; 21(5):471-7.
34. Baechler EC, Gregersen PK, Behrens TW. The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol. 2004; 16(6):801-7.
35. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5.
36. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003; 197(6):711-23.
37. Suh CH, Kim HA. Cytokines and their receptors as biomarkers of systemic lupus erythematosus. Expert Rev Mol Diagn. 2008; 8(2):189-98.
38. Lee PY, Reeves WH. Type I interferon as a target of treatment in SLE. Endocr Metab Immune Disord Drug Targets. 2006; 6(4):323-30.
39. Karonitsch T, Feierl E, Steiner CW, Dalwigk K, Korb A, Binder N, Rapp A, Steiner G, Scheinecker C, Smolen J, Aringer M. Activation of the interferon-gamma signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells. Arthritis Rheum. 2009; 60(5):1463-71.
40. Martinez-Lostao L, Ordi-Ros J, Balada E, Segarra-Medrano A, Majó-Masferrer J, Labrador-Horrillo M, Vilardell-Tarrés M. Activation of the signal transducer and activator of transcription-1 in diffuse proliferative lupus nephritis. Lupus. 2007; 16(7):483-8.
41. Dong J, Wang QX, Zhou CY, Ma XF, Zhang YC. Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus. 2007; 16(2):101-9.
42. Wang L, Tassiulas I, Park-Min KH, Reid AC, Gil-Henn H, Schlessinger J, Baron R, Zhang JJ, Ivashkiv LB. 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol. 2008; 9(2):186-93.
43. Sharabi A, Sthoeger ZM, Mahlab K, Lapter S, Zinger H, Mozes E. A tolerogenic peptide that induces suppressor of cytokine signaling (SOCS)-1 restores the aberrant control of IFN-gamma signaling in lupus-affected (NZB x NZW) F1 mice. Clin Immunol. 2009; 133(1):61-8.
44. Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, Kim SH, Park HS, Suh CH.Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol. 2007; 27(5):461-6.
45. Sabry A, Sheashaa H, El-Husseini A, Mahmoud K, Eldahshan KF, George SK, Abdel-Khalek E, El-Shafey EM, Abo-Zenah H. Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity. Cytokine. 2006; 35(3-4):148-53.
46. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007; 40(1):1-8.
47. Hale MB, Krutzik PO, Samra SS, Crane JM, Nolan GP. Stage dependent aberrant regulation of cytokine-STAT signaling in murine systemic lupus erythematosus. PLoS One. 2009; 4(8):e6756.
48. Pflegerl P, Vesely P, Hantusch B, Schlederer M, Zenz R, Janig E, Steiner G, Meixner A, Petzelbauer P, Wolf P, Soleiman A, Egger G, Moriggl R, Kishimoto T, Wagner EF, Kenner L. Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling. Proc Natl Acad Sci U S A. 2009; 106(48):20423-8.
49. Pramanik R, J?rgensen TN, Xin H, Kotzin BL, Choubey D. Interleukin-6 inducesexpression of Ifi202, an interferon-inducible candidate gene for lupus susceptibility. J Biol Chem. 2004; 279(16):16121-7.
50. Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY. Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology. 2006; 119(3):296-305.
51. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004; 202:139-56.
52. Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP, Jacob CO. Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol. 2003; 170(9):4818-25.
53. Li Z, Li Y, Huang L, Xu H, Yu X, Ye R. Expression of interleukin-12 and its signaling molecules in peripheral blood mononuclear cells in systemic lupus erythematosus patients. Chin Med J (Engl). 2002; 115(6):846-50.
54. Xu Z, Duan B, Croker BP, Morel L. STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol. 2006; 120(2):189-98.
55. Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol. 2009; 182(1):34-8.
56. Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, Ye DQ. A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol. 2010. [Epub ahead of print]
57. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, Gao F, Zhang PL, Guo Q, Li B,Gao M, Xiao FL, Quan C, Zhang C, Zhang Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009; 41(11):1234-7.
58. Kawasaki A, Ito I, Hikami K, Ohashi J, Hayashi T, Goto D, Matsumoto I, Ito S, Tsutsumi A, Koga M, Arinami T, Graham RR, Hom G, Takasaki Y, Hashimoto H, Behrens TW, Sumida T, Tsuchiya N. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. Arthritis Res Ther. 2008; 10(5):R113.
59. Suarez-Gestal M, Calaza M, Endreffy E, Pullmann R, Ordi-Ros J, Domenico Sebastiani G, Ruzickova S, Jose Santos M, Papasteriades C, Marchini M, Skopouli FN, Suarez A, Blanco FJ, D'Alfonso S, Bijl M, Carreira P, Witte T, Migliaresi S, Gomez-Reino JJ, Gonzalez A; European Consortium of SLE DNA Collections. Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res Ther. 2009; 11(3):R69.
60. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007; 357(10):977-86.
61. Jacob CO, Zang S, Li L, Ciobanu V, Quismorio F, Mizutani A, Satoh M, Koss M. Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol. 2003; 171(3):1564-71.
62. Nguyen H, Hiscott J, Pitha PM. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 1997; 8(4):293-312.
63. Ozato K, Tailor P, Kubota T. The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem. 2007; 282(28):20065-9.
64. Savitsky D, Tamura T, Yanai H, Taniguchi T. Regulation of immunity and oncogenesis by the IRF transcription factor family. Cancer Immunol Immunother. 2010; 59(4):489-510.
65. Lohoff M, Gessner A, Bogdan C, R?llinghoff M. Experimental murine leishmaniasis and the Th1/Th2 cell concept. Tokai J Exp Clin Med. 1998; 23(6):347-50.
66.钱捷,沈南,郭桂梅,万年红,林燕,黄新芳,吴慧,陈顺乐.系统性红斑狼疮患者干扰素调节因子IRF1 IRF4 IRF8基因表达的研究.中华风湿病学杂志,2006;10(9):513-6.
67. Reilly CM, Olgun S, Goodwin D, Gogal RM Jr, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS. Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006; 36(5):1296-308.
68. Salloum R, Franek BS, Kariuki SN, Rhee L, Mikolaitis RA, Jolly M, Utset TO, Niewold TB. Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients. Arthritis Rheum. 2010; 62(2):553-61.
69. Akahoshi M, Nakashima H, Sadanaga A, Miyake K, Obara K, Tamari M, Hirota T, Matsuda A, Shirakawa T. Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus. Lupus. 2008; 17(6):568-74.
70. Sánchez E, González-Gay MA, Callejas-Rubio JL, Ortego-Centeno N, Sabio JM, Jiménez-Alonso J, MicóL, Suarez A, Gutierrez C, de Ramón E, Camps M, Garcia-Portales R, Tolosa C, López-Nevot MA, Sánchez-Román J, Hernández FJ, González-Escribano MF, Martín J. No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus. Lupus. 2009; 18(3):230-4.
71. Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK.Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008; 58(8):2481-7.
72. Lee YH, Song GG. Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis. Rheumatol Int. 2009; 29(10):1137-42.
73. Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, Hirankarn N, Ying D, Pan HF, Mok CC, Chan TM, Wong RW, Lee KW, Mok MY, Wong SN, Leung AM, Li XP, Avihingsanon Y, Wong CM, Lee TL, Ho MH, Lee PP, Chang YK, Li PH, Li RJ, Zhang L, Wong WH, Ng IO, Lau CS, Sham PC, Lau YL; Asian Lupus Genetics Consortium. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010; 6(2):e1000841.
74. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G, Syv?nen AC, R?nnblom L, Barnes BJ. Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2010; 62(2):562-73.
75. Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, Merrill JT, James JA, Frank SG, Reams E, Brown EE, Gibson AW, Marion MC, Langefeld CD, Li QZ, Karp DR, Wakeland EK, Petri M, Ramsey-Goldman R, Reveille JD, ViláLM, Alarcón GS, Kimberly RP, Harley JB, Edberg JC. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun. 2008; 9(3):187-94.
76. Sigurdsson S, Nordmark G, G?ring HH, Lindroos K, Wiman AC, Sturfelt G, J?nsen A, Rantap??-Dahlqvist S, M?ller B, Kere J, Koskenmies S, Widén E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, R?nnblom L, Syv?nen AC. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes areassociated with systemic lupus erythematosus. Am J Hum Genet. 2005; 76(3):528-37.
77. Kyogoku C, Morinobu A, Nishimura K, Sugiyama D, Hashimoto H, Tokano Y, Mimori T, Terao C, Matsuda F, Kuno T, Kumagai S. Lack of association between tyrosine kinase 2 (TYK2) gene polymorphisms and susceptibility to SLE in a Japanese population. Mod Rheumatol. 2009; 19(4):401-6.
78. Hellquist A, J?rvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, Panelius J, Hasan T, Julkunen H, D'Amato M, Saarialho-Kere U, Kere J. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol. 2009; 36(8):1631-8.
79. Suarez-Gestal M, Calaza M, Gonzalez A. Lack of interaction between systemic lupus erythematosus-associated polymorphisms in TYK2 and IRF5. J Rheumatol. 2010; 37(3): 676-7.
80. Firestein GS. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol. 2005; 11(3 Suppl):S39-44.
81. Okamoto H, Hoshi D, Kiire A, Yamanaka H, Kamatani N. Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets. 2008; 7(1):53-66.
82. Taylor PC. Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. Curr Pharm Des. 2003; 9(14):1095-106.
83. Walker JG, Smith MD. The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol. 2005; 32(9):1650-3.
84. Yokota A, Narazaki M, Shima Y, Murata N, Tanaka T, Suemura M, Yoshizaki K, Fujiwara H, Tsuyuguchi I, Kishimoto T. Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells. J Rheumatol. 2001; 28(9):1952-9.
85. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJ, Kraan MC, Fero M, Tak PP, Huizinga TW, Pieterman E, Breedveld FC, AlizadehAA, Verweij CL. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003; 4 8(8):2132-45.
86. Isom?ki P, Alan?r? T, Isohanni P, Lagerstedt A, Korpela M, Moilanen T, Visakorpi T, Silvennoinen O. The expression of SOCS is altered in rheumatoid arthritis. Rheumatology (Oxford). 2007; 46(10):1538-46.
87. de Hooge AS, van de Loo FA, Koenders MI, Bennink MB, Arntz OJ, Kolbe T, van den Berg WB. Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice. Arthritis Rheum. 2004; 50(6):2014-23.
88. Wong PK, Egan PJ, Croker BA, O'Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest. 2006; 116(6):1571-81.
89. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJ, Kraan MC, Fero M, Tak PP, Huizinga TW, Pieterman E, Breedveld FC, Alizadeh AA, Verweij CL. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003; 48(8):2132-45.
90. Wang F, Sengupta TK, Zhong Z, Ivashkiv LB. Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J Exp Med. 1995; 182(6):1825-31.
91.杨馨,李继书,杨慎峭,张新星,张天生,周海燕,刘旭光.艾灸对实验性类风湿性关节炎家兔滑膜细胞JAK-STAT信号通路影响的研究.针刺研究. 2007; 32(4):75-82.
92. Hildner KM, Schirmacher P, Atreya I, Dittmayer M, Bartsch B, Galle PR, Wirtz S,Neurath MF. Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J Immunol. 2007; 178(6):3427-36.
93. Finnegan A, Grusby MJ, Kaplan CD, O'Neill SK, Eibel H, Koreny T, Czipri M, Mikecz K, Zhang J. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol. 2002; 169(6):3345-52.
94. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest. 2001; 108(5):739-47.
95. Boyton RJ, Davies S, Marden C, Fantino C, Reynolds C, Portugal K, Dewchand H, Altmann DM. Stat4-null non-obese diabetic mice: protection from diabetes and experimental allergic encephalomyelitis, but with concomitant epitope spread. Int Immunol. 2005; 17(9):1157-65.
96. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2010; 30(5):661-6.
97. Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MA, Balsa A, Pascual-Salcedo D, Fernández-Gutierrez B, González-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcón-Riquelme M, Martín J. Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum. 2008; 58(7):1974-80.
98. Zervou MI, Sidiropoulos P, Petraki E, Vazgiourakis V, Krasoudaki E, Raptopoulou A, Kritikos H, Choustoulaki E, Boumpas DT, Goulielmos GN. Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population. Hum Immunol. 2008; 69(9):567-71.
99. Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, Nakamura Y, Toyama Y, Mochizuki T, Tsukahara S, Kawaguchi Y, Terai C, Hara M, Tomatsu T, Yamanaka H, Horiuchi T, Tao K, Yasutomo K, Hamada D, Yasui N, Inoue H, Itakura M, Okamoto H, Kamatani N, Momohara S. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum. 2008; 58(7):1940-6.
100. Martínez A, VaradéJ, Márquez A, Cénit MC, Espino L, Perdigones N, Santiago JL, Fernández-Arquero M, de la Calle H, Arroyo R, Mendoza JL, Fernández-Gutiérrez B, de la Concha EG, Urcelay E. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum. 2008; 58(9):2598-602.
101.Finnegan A, Grusby MJ, Kaplan CD, O'Neill SK, Eibel H, Koreny T, Czipri M, Mikecz K, Zhang J. IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol. 2002 Sep 15; 169(6):3345-52.
102.Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009; 94(9):3171-82.
103.Peng SL. Transcription factors in autoimmune diseases. Front Biosci. 2008; 13:4218-40.
104.Litherland SA, Grebe KM, Belkin NS, Paek E, Elf J, Atkinson M, Morel L, Clare-Salzler MJ, McDuffie M. Nonobese diabetic mouse congenic analysis reveals chromosome 11 locus contributing to diabetes susceptibility, macrophage STAT5 dysfunction, and granulocyte-macrophage colony-stimulating factor overproduction. J Immunol. 2005; 175 (7):4561-5.
105.Yang Z, Chen M, Ellett JD, Fialkow LB, Carter JD, McDuffie M, Nadler JL. Autoimmune diabetes is blocked in Stat4-deficient mice. J Autoimmun. 2004; 22(3):191-200.
106.Homann D, Holz A, Bot A, Coon B, Wolfe T, Petersen J, Dyrberg TP, Grusby MJ, von Herrath MG. Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. Immunity. 1999; 11(4):463-72.
107.Zheng SJ, Lamhamedi-Cherradi SE, Wang P, Xu L, Chen YH. Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function. Diabetes. 2005; 54(5):1423-8.
108.Kim S, Kim HS, Chung KW, Oh SH, Yun JW, Im SH, Lee MK, Kim KW, Lee MS. Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice. Diabetes. 2007; 56(10):2561-8.
109.Chong MM, Thomas HE, Kay TW. Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem. 2002; 277(31):27945-52.
110.Mori H, Shichita T, Yu Q, Yoshida R, Hashimoto M, Okamoto F, Torisu T, Nakaya M, Kobayashi T, Takaesu G, Yoshimura A. Suppression of SOCS3 expression in the pancreatic beta-cell leads to resistance to type 1 diabetes. Biochem Biophys Res Commun. 2007; 359(4):952-8.
111.Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab. 2006; 17(9):365-71.
112.Lee HS, Park H, Yang S, Kim D, Park Y.STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci. 2008; 1150:93-8.
113.Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009; 361(21):2066-78.
114.Mudter J, Neurath MF. The role of signal transducers and activators of transcription in inflammatory bowel diseases. Inflamm Bowel Dis. 2003; 9(5):332-7.
115.Mudter J, Weigmann B, Bartsch B, Kiesslich R, Strand D, Galle PR, Lehr HA,Schmidt J, Neurath MF. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol. 2005; 100(1):64-72.
116.Pang YH, Zheng CQ, Yang XZ, Zhang WJ. Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cell Immunol. 2007; 248(2):115-20.
117.Parrello T, Monteleone G, Cucchiara S, Monteleone I, Sebkova L, Doldo P, Luzza F, Pallone F. Up-regulation of the IL-12 receptor beta 2 chain in Crohn's disease. J Immunol. 2000; 165(12):7234-9.
118.Musso A, Dentelli P, Carlino A, Chiusa L, Repici A, Sturm A, Fiocchi C, Rizzetto M, Pegoraro L, Sategna-Guidetti C, Brizzi MF. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis. 2005; 11(2):91-8.
119.Han X, Sosnowska D, Bonkowski EL, Denson LA. Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Gastroenterology. 2005; 129(1):185-203.
120.Mitsuyama K, Matsumoto S, Masuda J, Yamasakii H, Kuwaki K, Takedatsu H, Sata M. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res. 2007; 27(6A):3749-56.
121.Ferguson LR, Han DY, Fraser AG, Huebner C, Lam WJ, Morgan AR, Duan H, Karunasinghe N. Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population. Mutat Res. 2010. [Epub ahead of print]
122.Cénit MC, Alcina A, Márquez A, Mendoza JL, Díaz-Rubio M, de Las Heras V, Izquierdo G, Arroyo R, Fernández O, de la Concha EG, Matesanz F, Urcelay E.STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun. 2010 [Epub ahead of print]
123.Sato K, Shiota M, Fukuda S, Iwamoto E, Machida H, Inamine T, Kondo S, Yanagihara K, Isomoto H, Mizuta Y, Kohno S, Tsukamoto K. Strong evidence of a combination polymorphism of the tyrosine kinase 2 gene and the signal transducer and activator of transcription 3 gene as a DNA-based biomarker for susceptibility to Crohn's disease in the Japanese population. J Clin Immunol. 2009; 29(6):815-25.
124.Diaz-Gallo LM, Palomino-Morales RJ, Gómez-García M, Carde?a C, Rodrigo L, Nieto A, Alcain G, Cueto I, López-Nevot MA, Martin J. STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: A replication study. Hum Immunol. 2010. [Epub ahead of print]
125.Cannella B, Raine CS. Multiple sclerosis: cytokine receptors on oligodendrocytes predict innate regulation. Ann Neurol. 2004; 55(1):46-57.
126.Land KJ, Moll JS, Kaplan MH, Seetharamaiah GS. Signal transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in Graves' hyperthyroidism. Endocrinology. 2004; 145(8):3724-30.
127.Jackson M, Howie SE, Weller R, Sabin E, Hunter JA, McKenzie RC. Psoriatic keratinocytes show reduced IRF-1 and STAT-1alpha activation in response to gamma-IFN. FASEB J. 1999; 13(3):495-502.
128.Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, Itami S, Nickoloff BJ, DiGiovanni J.Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med. 2005; 11(1):43-9.
129.Tayal V, Kalra BS.Cytokines and anti-cytokines as therapeutics--an update. Eur J Pharmacol. 2008; 579(1-3):1-12.
130.Jo D, Liu D, Yao S, Collins RD, Hawiger J.Intracellular protein therapy withSOCS3 inhibits inflammation and apoptosis. Nat Med. 2005; 11(8):892-8.
131.Yamamoto M, Nishimoto N, Davydova J, Kishimoto T, Curiel DT. Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells. Cancer Gene Ther. 2006; 13(2):194-202.
132.王克明,王彬. JAK/STAT通路阻断剂AG490的研究现状.现代泌尿外科杂志. 2003;8(1):57-9.
133.Caceres-Cortes JR. A potent anti-carcinoma and anti-acute myeloblastic leukemia agent, AG490. Anticancer Agents Med Chem. 2008; 8(7):717-22.
134.S?emann MD, B?hmig GA, Osterreicher CH, Staffler G, Diakos C, Krieger PM, H?rl WH, Stockinger H, Zlabinger GJ.Suppression of primary T-cell responses and induction of alloantigen-specific hyporesponsiveness in vitro by the Janus kinase inhibitor tyrphostin AG490. Transplantation. 2000; 70(8):1215-25.
135.高薇,杨娉婷,沈晖,鲁静,肖卫国,赵丽娟.阻断JAK2STAT信号通路对大鼠类风湿关节炎治疗作用的实验研究.中国实用内科杂志. 2007;27(11):872-5.
136.Changelian PS, Moshinsky D, Kuhn CF, Flanagan ME, Munchhof MJ, Harris TM, Whipple DA, Doty JL, Sun J, Kent CR, Magnuson KS, Perregaux DG, Sawyer PS, Kudlacz EM. The specificity of JAK3 kinase inhibitors. Blood. 2008; 111(4):2155-7.
© 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 |