内质网应激和ARMET蛋白在免疫性关节炎症中的作用研究
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摘要
内质网应激(endoplasmic reticulum stress,ER stress)是真核细胞的一种保护性应激反应,通过激活未折叠蛋白反应(unfolded protein response,UPR)通路来减少细胞内蛋白的异常聚集,从而起到细胞保护作用。ER应激与很多因素所致疾病的发生、发展密切相关,越来越多的证据表明,ER应激及其UPR通路可能参与机体的炎症免疫反应。ARMET(arginine-rich, mutated in early stage tumors)基因是我们从30000个基因中筛选出的对ER应激最敏感的基因,它是一种分泌性蛋白,ER应激能诱导其表达上调。故我们推测,ARMET的诱导表达可能是细胞自身的保护性调节,那么在炎症诱导的ER应激中,ARMET可能起到抑制炎症的作用。
目的:
在免疫性关节炎动物模型上,观察炎症诱导的ER应激及ARMET的表达情况,分析ARMET表达与炎症程度的相关性,初步探讨ER应激及ARMET表达在免疫性关节炎症中的作用。
方法:
用甲基化牛血清白蛋白(methylated bovine serum albumin,mBSA)诱导兔关节炎(antigen-induced arthritis,AIA)模型,核磁共振成像(magnetic resonance imaging,MRI)扫描造模前后滑膜组织增厚情况,苏木素-伊红(hematoxylin-erosin,HE)染色观察滑膜组织病理改变;注射弗氏完全佐剂(Freund's complete adjuvant,FCA)建立大鼠佐剂性关节炎(adjuvant arthritis,AA)模型,足容积法测量继发侧足肿胀度,关节炎指数(arthritis index,AI)评分记录AA的发生及严重程度,HE染色观察关节组织病理学变化;分离培养成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)和腹腔巨噬细胞(peritoneal macrophage,PMΦ);ARMET真核细胞表达质粒pCIneo-ARMET-FLAG,ARMET小干扰RNA(small interfering RNA,siRNA)分别转染体外培养的FLS;MTT法检测细胞增殖活性;免疫荧光染色观察细胞形态和蛋白定位;逆转录聚合酶链反应(Reverse Transcription Polymerase Chain Reaction,RT-PCR)和免疫印迹(Western Blot,WB)分别检测相关基因在mRNA及蛋白水平的变化;放射免疫测定法(Radioimmunoassay,RIA)检测细胞培养上清中白介素-1β(interlukin-1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)水平;ELISA检测血清中ARMET、C-反应蛋白(C- reactive protein,CRP)、IL-1β及TNF-α水平。
结果:
1.免疫性关节炎动物模型的建立与评价
1.1 mBSA诱导的兔关节炎模型的建立:关节腔内注射mBSA后,模型组兔出现明显的关节炎表现,膝关节红肿,活动受限;MRI扫描发现膝关节滑膜明显增厚,关节腔变窄;病理改变表现为滑膜组织增生,新生血管形成,炎性细胞浸润等;炎症滑膜组织中巨噬细胞的标志性蛋白白细胞分化抗原68(Cluster of Differentiation 68,CD68)和成肌纤维细胞的标志物平滑肌肌动蛋白α(α-smooth muscle actin,α-SMA)的表达明显增强;
1.2大鼠AA模型的建立:AA大鼠致炎后d3～d12,表现为原发侧关节肿胀,行走不便,食欲减退,d12后出现继发侧关节肿胀,耳,尾出现炎性结节和红斑并伴有多发性全身关节病变,病理改变表现为膝关节滑膜组织增生,新生血管增多,血管翳形成,关节腔内可见淋巴细胞、浆细胞和单核细胞聚集,软骨和骨组织破坏等关节局部病理变化;外周血血清中TNF-α、IL-1β水平明显升高。以上结果提示mBSA诱导的兔关节炎和大鼠AA模型制备成功。
2.免疫性关节炎症诱导的ER应激参与了炎症反应过程
2.1炎症诱导ER应激:炎症滑膜组织中BiP的mRNA和蛋白水平明显增加,且在FLS、MLS中都有表达; AA大鼠PMΦ中BiP表达也明显增加,提示免疫性关节炎症能诱导滑膜细胞和PMΦ的ER应激。核转录因子CHOP在炎症滑膜组织中的表达略有增高,且仅表达于FLS,在MLS中不表达;而AA大鼠PMΦ中CHOP表达却明显增加,提示巨噬细胞的不同功能状态对ER应激的反应性不同。同时我们还发现模型组滑膜组织中滑膜素(Synoviolin/Hrd1)的mRNA和蛋白水平均明显增加,提示免疫性关节炎症能上调Synoviolin的表达。
2.2 ER应激促进关节炎症进展:与正常FLS相比,模型组FLS的增殖能力明显增强,ER应激诱导剂tunicamycin能显著降低正常FLS的增殖,而对炎症FLS的增殖无明显影响,提示FLS对ER应激性损伤的敏感性下降,这可能是ER应激状态下滑膜细胞异常增殖的原因之一。另外,tunicamycin能促进炎症FLS中IL-1β,TNF-α的表达和分泌,从而进一步促进了滑膜细胞的异常增殖。
3.免疫性关节炎症诱导ARMET表达及其与炎症程度的相关性3.1炎症诱导ARMET表达:在炎性增厚的滑膜组织中ARMET大量表达,且主
要定位于α-SMA阳性细胞,在CD68阳性细胞中几乎不表达;而AA大鼠PMΦ中ARMET的表达明显增加,提示关节炎症能诱导ARMET表达,并且不同组织来源的巨噬细胞对ER应激的反应性不同。
3.2炎症不同时期滑膜组织中ER应激及ARMET的表达情况:致炎后不同时期收集AA大鼠滑膜组织进行RT-PCR和WB检测,结果发现急性炎症期(d2左右)BiP表达明显升高,此后一直维持在较高的水平,到d28稍有下降;致炎d14左右ARMET表达明显升高,随后逐渐下降;而CHOP则一直维持在低水平缓慢上升的状态,提示ARMET参与了AA炎症反应的全过程,且对炎症刺激更为敏感。
3.3炎症不同时期外周血中ARMET水平与炎症程度的相关性:致炎后d14,ARMET水平显著增高,随后逐渐下降,d28仍高于正常水平;同样,血清中CRP水平在致炎后一周内即明显升高,d14左右达到峰值,随后缓慢下降,与ARMET的变化趋势基本一致。相关性分析表明,AA大鼠血清中ARMET水平与继发性关节炎症状、血清中IL-1β和TNF-α水平呈负相关。提示炎症能诱导ARMET分泌,且血清中ARMET水平与关节炎症进展和程度密切相关。
4. ARMET对成纤维样滑膜细胞增殖和炎症细胞因子产生的影响
4.1 ARMET表达对FLS增殖的影响:ARMET过表达能抑制ER应激状态下FLS的增殖;下调内源性ARMET表达后,FLS的增殖能力增强;在体外培养的FLS中加入重组的人ARMET蛋白能剂量依赖性的抑制炎症滑膜细胞的增殖;
4.2 ARMET表达对FLS表达和分泌IL-1β、TNF-α的影响:下调内源性ARMET表达使FLS表达和分泌IL-1β和TNF-α水平增加;而重组的人ARMET蛋白能剂量依赖性的降低FLS中IL-1β和TNF-α的表达和分泌。
5.炎症诱导ARMET的核转运
在AIA兔滑膜组织中,我们观察到ARMET在FLS中的定位与α-SMA表达量有关。α-SMA少量表达时,ARMET分布在胞浆中;而α-SMA大量表达时,细胞核内也有ARMET表达;体外培养的AA大鼠FLS中,未经tunicamycin处理的FLS中ARMET在胞核内表达很少,而在胞浆中含量较多;tunicamycin刺激24 hrs后,ARMET在细胞核内含量明显增多,而在胞浆中表达减少。提示tuncamycin能够诱导滑膜细胞中ARMET的核转运。
结论:
1)免疫性关节炎症能诱导ER应激,ER应激通过上调FLS中炎症因子的产生而起到促进炎症的作用;
2)免疫性关节炎症上调ARMET表达,并且滑膜组织中表达ARMET的细胞类型主要为FLS;
3) ARMET表达参与了AA大鼠炎症反应的全过程,且对早期炎症刺激敏感;
4) AA大鼠PMΦ参与了炎症诱导的ER应激和ARMET表达,提示巨噬细胞的不同功能状态对ER应激的反应性不同;
5) AA大鼠外周血中ARMET水平明显升高,并与继发性关节炎症状、血清中IL-1β、TNF-α和CRP水平具有相关性。提示炎症能诱导ARMET分泌,且血清中ARMET水平与关节炎症进展和程度密切相关。
6) ARMET能抑制炎症滑膜细胞的增殖、减少炎症因子的产生;并且该作用可能与炎症诱导滑膜细胞中ARMET的核转运,进而参与下游基因转录调控有关。
Rheumatoid arthritis (RA) is an inflammatory, progressive, destructive autoimmune disease with synovial hyperplasia followed by impairment of quality of life. However, its exact mechanism(s) is not fully understood. The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a fundamental stress response used by eukaryotic cells to match protein synthesis demand to its capability to fold proteins within the ER to maintain cellular homeostasis. A variety of human disorders, including neurodegenerative diseases, autoimmune diseases and diabetes mellitus, are known to involve ER stress. Recent studies have been proposed that ER stress and the related signal pathway maybe involved in the pathogenesis of RA. However, the crucial questions about the role of ER stress in inflammation response of RA have not yet been answered. Armet (Arginine-Rich, Mutated in Early stage Tumors) gene is a commonly upregulated genes under various forms of ER stress in different cell types using microarray analysis. The recent studies show ARMET to be a secreted protein, and ER stress upregulates its expression and secretion. It was also found that ARMET is widely expressed in mammalian tissues and differently regulated by epileptic and ischemic insults in rodent brain and heart. These results suggest that ARMET may have important functions both under normal and pathological conditions. Therefore, we speculate up-regulated ARMET expression may be self-protective regulation, then, ARMET may play a role in inhibiting inflammation under inflammation-induced ER stress status.
Objective:
The purposes of this study were to investigate the ER stress activation and ARMET expression in antigen-induced arthritis model, analysis the relationship between ARMET expression and inflammation evolution. Furthermore, the possible effects of ER stress and ARMET on inflammation in antigen-induced arthritis were also explored.
Methods:
Methylated bovine serum albumin (mBSA) and Freund’s complete adjuvant (FCA) were employed to establish rabbit AIA model. Joint lesions were assessed by MRI and hematoxylin-erosin (HE) staining. Injection of FCA in rats was employed to establish AA model, hind paw volumes of rats were measured by volume meter, arthritis index (AI) was assayed every two days after immunization, pathological changes were observed by HE staining. Fibroblasts-like synovial cells (FLS) and peritoneal macrophage (PMΦ) were isolated and cultured at 37°C with 5% CO2. Small interference RNA for ARMET was systhesized from Genepharm. Co. LTD. Synoviocytes were then transfected with pCIneo-ARMET-FLAG or siRNA-ARMET respectively. MTT assay was used to determine cell proliferation. Cell morphologies and intracellular protein localization were examed by immunocytochemistry and immunofluorescence. Reverse transcription polymerase chain reaction (RT-PCR) and western blot (WB) were used to detect mRNA and protein level respectively. Radioimmunoassay (RIA) was used to detect the levels of pro-inflammatory cytokines IL-1βand TNF-αsecreted by FLS. ELISA assay was used to determine the levels of ARMET、IL-1β、TNF-αand CRP in peripheral blood serum of AA rats.
Results:
1. Establishment of antigen-induced arthritis model
1.1 mBSA induced rabbit arthritis model: In the arthritis model group, MRI scanning showed marked thickening of joint synoviums. HE staining showed synovium thickening and inflammatory cells infiltration. The expressions of CD68 (activated macrophage marker) and fibroblast markerα-SMA were significantly increased in AIA rabbit synoviums.
1.2 AA rat model: AA rats were established and hind volumes of rats were measured by volume meter. Inflammatory polyarthritis was induced in all immunization. Synoviocytes were proliferated three to ten layers and articular cartilages were destructed and infiltrated with inflammatory cells. The levels of TNF-αand IL-1βin peripheral blood serum of AA rats significantly increased. Above results suggest that arthritis models were established successfully.
2. Diverse regulation of synovium inflammation by ER stress inducible proteins in antigen-induced arthritis
2.1 ER stress-related proteins were upregulated in antigen-induced arthritis: BiP expression was remarkably up-regulated in thickened synoviums, while the total level of CHOP was slightly increased in the AA synovium. Additionally, unlike BiP expressing in bothα-SMA-positive fibroblasts and CD68-positive microphages, CHOP expression only was induced inα-SMA-positive fibroblasts, but not CD68-positive microphages. We also observed expressions of BiP and CHOP in PMΦderived from AA rats.
2.2 Effects of ER stress on FLS proliferation and cytokine production:ER stress inducer tunicamycin significantly decreased the proliferation of normal FLS, while have little effect on proliferation of inflammatory FLS. Furthermore, Synoviolin was remarkably up-regulated in thickened synovial membrane, suggested inflammatory FLS overexpressing Synoviolin can resistance to ER stress-induced cell death. Additionally, tunicamycin significantly increases the expression and secretion of inflammatory cytokines IL-1β, TNF-αin AIA rabbits-derived FLS. These results suggest that ER stress response may be induced in the inflammatory status, which may contribute to the pathogenesis of AA by increased expression of genes encoding pro-inflammatory cytokines.
3. Characteristics and implication of ARMET expression in antigen-induced arthritis
3.1 Inflammation up-regulated ARMET expression : ARMET expression was remarkably up-regulated in inflammatory synovial tissue compared to normal controls. More interestingly, ARMET expression only was induced inα-SMA-positive fibroblasts, but not CD68-positive microphages. We also observed ARMET expression in PMΦderived from AA rats. These results suggest that inflammation up-regulated ARMET expression in FLS and PMΦ.
3.2 Induction profile of ER stress and ARMET expression in synovial tissue during different phases of inflammation:BiP expression was increased significantly early in primary inflammation response (d2 ~ d7), then remained at a high level, then decreased slightly until d28; expression of ARMET showed a significant increase at d14 and then decreased slightly. CHOP expression increased slowly during inflammation development.
3.3 The level of ARMET in peripheral blood serum is correlated with the degree of arthritis inflammation. The levels of ARMET in peripheral blood serum of AA rats increased significantly at d14, while serum CRP also exhibited a similar trend of expression. Correlation analysis revealed that arthritis symptoms, serum IL-1β, TNF-αlevels were negatively correlated with the level of ARMET during second inflammation phase.
4. Effects of ARMET on FLS proliferation and inflammatory cytokine production Over-expression of ARMET inhibited cell proliferation under ER stress status. Inhibition of endogenous ARMET expression increased cell proliferation, promoted IL-1β、TNF-αexpression and secretion in AA rats-derived FLS. Similarly, exogenous ARMET protein can dose-dependently inhibited cell proliferation, and reduced IL-1βand TNF-αexpression and secretion in AA rats-derived FLS.
5. ER stress induces nuclear translocation of ARMET in FLS Intriguingly,ARMET was found expressed in the nucleus of FLS whileα-SMA activated greatly, and tunicamycin induced nuclear translocation of ARMET in FLS. The data ruled out the possibility that ARMET is activated under ER stress and translocated to nucleus as a transcription factor,regulates downstream gene expression through specific binding with promoter sequences.
Conclusions:
1. ER stress may be induced by inflammation, which may contribute to the pathogenesis of arthritis by increased expression and secretion of pro-inflammatory cytokines;
2. Inflammation up-regulated ARMET expression, and fibroblasts of the myofibroblastic phenotype seem to be the major cell type expressing ARMET in synovial tissues;
3. ARMET is involved in the development of AA and more sensitive to inflammatory stimulus than BiP and CHOP;
4. Inflammation induced ER stress and ARMET expression in AA PMΦ, suggesting different tissues-derived macrophages exhibited different responses to ER stress;
5. The level of ARMET in PB of AA rats is increased and correlated with arthritis symptoms, pro-inflammatory cytokine, and CRP, suggesting ARMET is closely related to the progression of arthritis;
6. ARMET plays a protective role in controlling inflammation through inhibiting synoviocytes proliferation and inflammatory cytokines production, and these effects may related to ER stress induced nuclear translocation of ARMET.
目的:
在免疫性关节炎动物模型上,观察炎症诱导的ER应激及ARMET的表达情况,分析ARMET表达与炎症程度的相关性,初步探讨ER应激及ARMET表达在免疫性关节炎症中的作用。
方法:
用甲基化牛血清白蛋白(methylated bovine serum albumin,mBSA)诱导兔关节炎(antigen-induced arthritis,AIA)模型,核磁共振成像(magnetic resonance imaging,MRI)扫描造模前后滑膜组织增厚情况,苏木素-伊红(hematoxylin-erosin,HE)染色观察滑膜组织病理改变;注射弗氏完全佐剂(Freund's complete adjuvant,FCA)建立大鼠佐剂性关节炎(adjuvant arthritis,AA)模型,足容积法测量继发侧足肿胀度,关节炎指数(arthritis index,AI)评分记录AA的发生及严重程度,HE染色观察关节组织病理学变化;分离培养成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)和腹腔巨噬细胞(peritoneal macrophage,PMΦ);ARMET真核细胞表达质粒pCIneo-ARMET-FLAG,ARMET小干扰RNA(small interfering RNA,siRNA)分别转染体外培养的FLS;MTT法检测细胞增殖活性;免疫荧光染色观察细胞形态和蛋白定位;逆转录聚合酶链反应(Reverse Transcription Polymerase Chain Reaction,RT-PCR)和免疫印迹(Western Blot,WB)分别检测相关基因在mRNA及蛋白水平的变化;放射免疫测定法(Radioimmunoassay,RIA)检测细胞培养上清中白介素-1β(interlukin-1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)水平;ELISA检测血清中ARMET、C-反应蛋白(C- reactive protein,CRP)、IL-1β及TNF-α水平。
结果:
1.免疫性关节炎动物模型的建立与评价
1.1 mBSA诱导的兔关节炎模型的建立:关节腔内注射mBSA后,模型组兔出现明显的关节炎表现,膝关节红肿,活动受限;MRI扫描发现膝关节滑膜明显增厚,关节腔变窄;病理改变表现为滑膜组织增生,新生血管形成,炎性细胞浸润等;炎症滑膜组织中巨噬细胞的标志性蛋白白细胞分化抗原68(Cluster of Differentiation 68,CD68)和成肌纤维细胞的标志物平滑肌肌动蛋白α(α-smooth muscle actin,α-SMA)的表达明显增强;
1.2大鼠AA模型的建立:AA大鼠致炎后d3～d12,表现为原发侧关节肿胀,行走不便,食欲减退,d12后出现继发侧关节肿胀,耳,尾出现炎性结节和红斑并伴有多发性全身关节病变,病理改变表现为膝关节滑膜组织增生,新生血管增多,血管翳形成,关节腔内可见淋巴细胞、浆细胞和单核细胞聚集,软骨和骨组织破坏等关节局部病理变化;外周血血清中TNF-α、IL-1β水平明显升高。以上结果提示mBSA诱导的兔关节炎和大鼠AA模型制备成功。
2.免疫性关节炎症诱导的ER应激参与了炎症反应过程
2.1炎症诱导ER应激:炎症滑膜组织中BiP的mRNA和蛋白水平明显增加,且在FLS、MLS中都有表达; AA大鼠PMΦ中BiP表达也明显增加,提示免疫性关节炎症能诱导滑膜细胞和PMΦ的ER应激。核转录因子CHOP在炎症滑膜组织中的表达略有增高,且仅表达于FLS,在MLS中不表达;而AA大鼠PMΦ中CHOP表达却明显增加,提示巨噬细胞的不同功能状态对ER应激的反应性不同。同时我们还发现模型组滑膜组织中滑膜素(Synoviolin/Hrd1)的mRNA和蛋白水平均明显增加,提示免疫性关节炎症能上调Synoviolin的表达。
2.2 ER应激促进关节炎症进展:与正常FLS相比,模型组FLS的增殖能力明显增强,ER应激诱导剂tunicamycin能显著降低正常FLS的增殖,而对炎症FLS的增殖无明显影响,提示FLS对ER应激性损伤的敏感性下降,这可能是ER应激状态下滑膜细胞异常增殖的原因之一。另外,tunicamycin能促进炎症FLS中IL-1β,TNF-α的表达和分泌,从而进一步促进了滑膜细胞的异常增殖。
3.免疫性关节炎症诱导ARMET表达及其与炎症程度的相关性3.1炎症诱导ARMET表达:在炎性增厚的滑膜组织中ARMET大量表达,且主
要定位于α-SMA阳性细胞,在CD68阳性细胞中几乎不表达;而AA大鼠PMΦ中ARMET的表达明显增加,提示关节炎症能诱导ARMET表达,并且不同组织来源的巨噬细胞对ER应激的反应性不同。
3.2炎症不同时期滑膜组织中ER应激及ARMET的表达情况:致炎后不同时期收集AA大鼠滑膜组织进行RT-PCR和WB检测,结果发现急性炎症期(d2左右)BiP表达明显升高,此后一直维持在较高的水平,到d28稍有下降;致炎d14左右ARMET表达明显升高,随后逐渐下降;而CHOP则一直维持在低水平缓慢上升的状态,提示ARMET参与了AA炎症反应的全过程,且对炎症刺激更为敏感。
3.3炎症不同时期外周血中ARMET水平与炎症程度的相关性:致炎后d14,ARMET水平显著增高,随后逐渐下降,d28仍高于正常水平;同样,血清中CRP水平在致炎后一周内即明显升高,d14左右达到峰值,随后缓慢下降,与ARMET的变化趋势基本一致。相关性分析表明,AA大鼠血清中ARMET水平与继发性关节炎症状、血清中IL-1β和TNF-α水平呈负相关。提示炎症能诱导ARMET分泌,且血清中ARMET水平与关节炎症进展和程度密切相关。
4. ARMET对成纤维样滑膜细胞增殖和炎症细胞因子产生的影响
4.1 ARMET表达对FLS增殖的影响:ARMET过表达能抑制ER应激状态下FLS的增殖;下调内源性ARMET表达后,FLS的增殖能力增强;在体外培养的FLS中加入重组的人ARMET蛋白能剂量依赖性的抑制炎症滑膜细胞的增殖;
4.2 ARMET表达对FLS表达和分泌IL-1β、TNF-α的影响:下调内源性ARMET表达使FLS表达和分泌IL-1β和TNF-α水平增加;而重组的人ARMET蛋白能剂量依赖性的降低FLS中IL-1β和TNF-α的表达和分泌。
5.炎症诱导ARMET的核转运
在AIA兔滑膜组织中,我们观察到ARMET在FLS中的定位与α-SMA表达量有关。α-SMA少量表达时,ARMET分布在胞浆中;而α-SMA大量表达时,细胞核内也有ARMET表达;体外培养的AA大鼠FLS中,未经tunicamycin处理的FLS中ARMET在胞核内表达很少,而在胞浆中含量较多;tunicamycin刺激24 hrs后,ARMET在细胞核内含量明显增多,而在胞浆中表达减少。提示tuncamycin能够诱导滑膜细胞中ARMET的核转运。
结论:
1)免疫性关节炎症能诱导ER应激,ER应激通过上调FLS中炎症因子的产生而起到促进炎症的作用;
2)免疫性关节炎症上调ARMET表达,并且滑膜组织中表达ARMET的细胞类型主要为FLS;
3) ARMET表达参与了AA大鼠炎症反应的全过程,且对早期炎症刺激敏感;
4) AA大鼠PMΦ参与了炎症诱导的ER应激和ARMET表达,提示巨噬细胞的不同功能状态对ER应激的反应性不同;
5) AA大鼠外周血中ARMET水平明显升高,并与继发性关节炎症状、血清中IL-1β、TNF-α和CRP水平具有相关性。提示炎症能诱导ARMET分泌,且血清中ARMET水平与关节炎症进展和程度密切相关。
6) ARMET能抑制炎症滑膜细胞的增殖、减少炎症因子的产生;并且该作用可能与炎症诱导滑膜细胞中ARMET的核转运,进而参与下游基因转录调控有关。
Rheumatoid arthritis (RA) is an inflammatory, progressive, destructive autoimmune disease with synovial hyperplasia followed by impairment of quality of life. However, its exact mechanism(s) is not fully understood. The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a fundamental stress response used by eukaryotic cells to match protein synthesis demand to its capability to fold proteins within the ER to maintain cellular homeostasis. A variety of human disorders, including neurodegenerative diseases, autoimmune diseases and diabetes mellitus, are known to involve ER stress. Recent studies have been proposed that ER stress and the related signal pathway maybe involved in the pathogenesis of RA. However, the crucial questions about the role of ER stress in inflammation response of RA have not yet been answered. Armet (Arginine-Rich, Mutated in Early stage Tumors) gene is a commonly upregulated genes under various forms of ER stress in different cell types using microarray analysis. The recent studies show ARMET to be a secreted protein, and ER stress upregulates its expression and secretion. It was also found that ARMET is widely expressed in mammalian tissues and differently regulated by epileptic and ischemic insults in rodent brain and heart. These results suggest that ARMET may have important functions both under normal and pathological conditions. Therefore, we speculate up-regulated ARMET expression may be self-protective regulation, then, ARMET may play a role in inhibiting inflammation under inflammation-induced ER stress status.
Objective:
The purposes of this study were to investigate the ER stress activation and ARMET expression in antigen-induced arthritis model, analysis the relationship between ARMET expression and inflammation evolution. Furthermore, the possible effects of ER stress and ARMET on inflammation in antigen-induced arthritis were also explored.
Methods:
Methylated bovine serum albumin (mBSA) and Freund’s complete adjuvant (FCA) were employed to establish rabbit AIA model. Joint lesions were assessed by MRI and hematoxylin-erosin (HE) staining. Injection of FCA in rats was employed to establish AA model, hind paw volumes of rats were measured by volume meter, arthritis index (AI) was assayed every two days after immunization, pathological changes were observed by HE staining. Fibroblasts-like synovial cells (FLS) and peritoneal macrophage (PMΦ) were isolated and cultured at 37°C with 5% CO2. Small interference RNA for ARMET was systhesized from Genepharm. Co. LTD. Synoviocytes were then transfected with pCIneo-ARMET-FLAG or siRNA-ARMET respectively. MTT assay was used to determine cell proliferation. Cell morphologies and intracellular protein localization were examed by immunocytochemistry and immunofluorescence. Reverse transcription polymerase chain reaction (RT-PCR) and western blot (WB) were used to detect mRNA and protein level respectively. Radioimmunoassay (RIA) was used to detect the levels of pro-inflammatory cytokines IL-1βand TNF-αsecreted by FLS. ELISA assay was used to determine the levels of ARMET、IL-1β、TNF-αand CRP in peripheral blood serum of AA rats.
Results:
1. Establishment of antigen-induced arthritis model
1.1 mBSA induced rabbit arthritis model: In the arthritis model group, MRI scanning showed marked thickening of joint synoviums. HE staining showed synovium thickening and inflammatory cells infiltration. The expressions of CD68 (activated macrophage marker) and fibroblast markerα-SMA were significantly increased in AIA rabbit synoviums.
1.2 AA rat model: AA rats were established and hind volumes of rats were measured by volume meter. Inflammatory polyarthritis was induced in all immunization. Synoviocytes were proliferated three to ten layers and articular cartilages were destructed and infiltrated with inflammatory cells. The levels of TNF-αand IL-1βin peripheral blood serum of AA rats significantly increased. Above results suggest that arthritis models were established successfully.
2. Diverse regulation of synovium inflammation by ER stress inducible proteins in antigen-induced arthritis
2.1 ER stress-related proteins were upregulated in antigen-induced arthritis: BiP expression was remarkably up-regulated in thickened synoviums, while the total level of CHOP was slightly increased in the AA synovium. Additionally, unlike BiP expressing in bothα-SMA-positive fibroblasts and CD68-positive microphages, CHOP expression only was induced inα-SMA-positive fibroblasts, but not CD68-positive microphages. We also observed expressions of BiP and CHOP in PMΦderived from AA rats.
2.2 Effects of ER stress on FLS proliferation and cytokine production:ER stress inducer tunicamycin significantly decreased the proliferation of normal FLS, while have little effect on proliferation of inflammatory FLS. Furthermore, Synoviolin was remarkably up-regulated in thickened synovial membrane, suggested inflammatory FLS overexpressing Synoviolin can resistance to ER stress-induced cell death. Additionally, tunicamycin significantly increases the expression and secretion of inflammatory cytokines IL-1β, TNF-αin AIA rabbits-derived FLS. These results suggest that ER stress response may be induced in the inflammatory status, which may contribute to the pathogenesis of AA by increased expression of genes encoding pro-inflammatory cytokines.
3. Characteristics and implication of ARMET expression in antigen-induced arthritis
3.1 Inflammation up-regulated ARMET expression : ARMET expression was remarkably up-regulated in inflammatory synovial tissue compared to normal controls. More interestingly, ARMET expression only was induced inα-SMA-positive fibroblasts, but not CD68-positive microphages. We also observed ARMET expression in PMΦderived from AA rats. These results suggest that inflammation up-regulated ARMET expression in FLS and PMΦ.
3.2 Induction profile of ER stress and ARMET expression in synovial tissue during different phases of inflammation:BiP expression was increased significantly early in primary inflammation response (d2 ~ d7), then remained at a high level, then decreased slightly until d28; expression of ARMET showed a significant increase at d14 and then decreased slightly. CHOP expression increased slowly during inflammation development.
3.3 The level of ARMET in peripheral blood serum is correlated with the degree of arthritis inflammation. The levels of ARMET in peripheral blood serum of AA rats increased significantly at d14, while serum CRP also exhibited a similar trend of expression. Correlation analysis revealed that arthritis symptoms, serum IL-1β, TNF-αlevels were negatively correlated with the level of ARMET during second inflammation phase.
4. Effects of ARMET on FLS proliferation and inflammatory cytokine production Over-expression of ARMET inhibited cell proliferation under ER stress status. Inhibition of endogenous ARMET expression increased cell proliferation, promoted IL-1β、TNF-αexpression and secretion in AA rats-derived FLS. Similarly, exogenous ARMET protein can dose-dependently inhibited cell proliferation, and reduced IL-1βand TNF-αexpression and secretion in AA rats-derived FLS.
5. ER stress induces nuclear translocation of ARMET in FLS Intriguingly,ARMET was found expressed in the nucleus of FLS whileα-SMA activated greatly, and tunicamycin induced nuclear translocation of ARMET in FLS. The data ruled out the possibility that ARMET is activated under ER stress and translocated to nucleus as a transcription factor,regulates downstream gene expression through specific binding with promoter sequences.
Conclusions:
1. ER stress may be induced by inflammation, which may contribute to the pathogenesis of arthritis by increased expression and secretion of pro-inflammatory cytokines;
2. Inflammation up-regulated ARMET expression, and fibroblasts of the myofibroblastic phenotype seem to be the major cell type expressing ARMET in synovial tissues;
3. ARMET is involved in the development of AA and more sensitive to inflammatory stimulus than BiP and CHOP;
4. Inflammation induced ER stress and ARMET expression in AA PMΦ, suggesting different tissues-derived macrophages exhibited different responses to ER stress;
5. The level of ARMET in PB of AA rats is increased and correlated with arthritis symptoms, pro-inflammatory cytokine, and CRP, suggesting ARMET is closely related to the progression of arthritis;
6. ARMET plays a protective role in controlling inflammation through inhibiting synoviocytes proliferation and inflammatory cytokines production, and these effects may related to ER stress induced nuclear translocation of ARMET.
引文
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