The Role of Beta-Arrestins 1 and 2 in Rheumatoid Arthritis

促炎细胞因子和趋化因子在类风湿关节炎(RA)中起重要作用。最新研究 阐述了Toll样受体S在类风湿关节炎发生发展中的作用。一个重要的 各种TLRs在关节炎动物模型中的作用已得到证实。TLR4和内源性TLR4 透明质酸和热休克蛋白(HSP)22等配体在RA滑膜组织中高表达 患者与健康供者的比较进一步提示TLRs在RA发病机制中的作用。然而，这些信号 调节内源性TLR4配体诱导的类风湿关节炎TLR激活的途径尚不完全清楚。 最近的研究表明，适配器蛋白-arrestin 1和2与TRAF6、I和B有关。 NFb1p105负向调节TLR信号转导。我们的数据首次证明？-arrestin 2 在胶原抗体诱导的关节炎(CAIA)模型中，基因敲除(KO)小鼠表现出更严重的关节炎 与野生型(WT)小鼠相比。此外，我们还观察到α-arrestin 1和2的表达增加 胶原诱导性关节炎(CIA)小鼠脾细胞和成纤维细胞样滑膜细胞(FLS)的比较 对照组小鼠。也证明了内毒素和内源性TLR4配体的低分子量 透明质酸(LMW-HA)诱导的小鼠脾细胞产生的肿瘤坏死因子(TNF)、白介素6(IL-6)和白介素10(IL-10)增加。 Arrestin 2KO小鼠与WT小鼠比较。这些发现导致我们提出了上调调控的假设 α-arrestin 1和2表达通过负性抑制胶原性关节炎的炎症 炎性细胞反应的调节。具体目的是研究α-arrestin 1和2在AS中的作用。 胶原性关节炎炎症反应的负调节因子。？-arrestin 1和2在 脾巨噬细胞，CD_4和CD_8 T淋巴细胞，B淋巴细胞，树突状细胞S， 中性粒细胞S和FL S与小鼠CIA模型疾病严重程度的相关性 接受检查。一旦确定了表现出抑制素表达变化的特定免疫细胞， ？-arrestin 1和2的表达在这些细胞激活中的作用将使用慢病毒表达来检测。 用RNAi过表达抑制素或抑制抑制素的系统。了解阻滞剂依赖 调节促炎和抗炎基因表达的信号通路将为研究 类风湿性关节炎的发病机制，创新的靶向干预可以从中进化。

Pro-inflammatory cytokines and chemokines play critical roles in rheumatoid arthritis (RA). Recent studies have addressed the role of toll-like receptors (TLR)s in the development and progression of RA. An important role of various TLRs in the animal model of arthritis has been demonstrated. TLR4 and endogenous TLR4 ligands such as hyaluronan and heat shock protein (HSP)22 are highly expressed in synovial tissue from RA patients compared with healthy donors further implicating TLRs in RA pathogenesis. However the signaling pathways that regulate endogenous TLR4 ligands-induced TLR activation in RA are not fully understood. Recent studies demonstrated that adaptor proteins ¿-arrestin 1 and 2 associating with TRAF6, I¿B¿, and NF¿B1p105 negatively regulate TLR signaling. Our data demonstrated for the first time that ¿-arrestin 2 knockout (KO) mice exhibited more severe arthritis in the collagen antibody-induced arthritis (CAIA) model compared to wild type (WT) mice. Furthermore, we observed that ¿-arrestin 1 and 2 expression are increased in splenocytes and fibroblast-like synoviocytes (FLS) in the collagen-induced arthritis (CIA) mice compared to the control mice. It was also demonstrated that LPS- and the endogenous TLR4 ligand low molecular weight hyaluronan (LMW-HA)- induced TNF¿, IL-6 and IL-10 production were augmented in splenocytes from ¿- arrestin 2 KO mice compared to WT mice. These findings led us to propose the hypothesis that up-regulation of ¿-arrestin 1 and 2 expression suppresses inflammation in collagen-induced arthritis by negative regulation of inflammatory cell responses. The specific aim is to investigate the role of ¿-arrestin 1 and 2 as negative regulators of the inflammatory response in collagen-induced arthritis. ¿-arrestin 1 and 2 expression in splenic macrophages, CD4+ and CD8+ T lymphocytes, B lymphocytes, dendritic cells (DC)s, polymorphonuclear leukocyte (PMN)s and FLS correlation to the disease severity in the mouse CIA model will be examined. Once the specific immune cells that exhibit altered expression of ¿-arrestins are identified, the role of ¿-arrestin 1 and 2 expression on activation of these cells will be examined using the lentiviral expression system to overexpress ¿-arrestins or knock down ¿-arrestins with RNAi. Understanding ¿-arrestins-dependent signaling pathways that regulate pro- and anti-inflammatory gene expression will provide novel insights into the pathogenesis of RA from which innovative targeted interventions can evolve.