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

Beta-Arrestins 1 和 2 在类风湿关节炎中的作用

基本信息

批准号：
8097660
负责人：
Hongkuan Fan
金额：
$ 5.29万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-02 至 2011-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097660
关键词：
Adaptor Signaling Protein Address Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Arrestin Beta 1 Arrestins Arthritis Autoimmune Diseases B-Lymphocytes CD8-Positive T-Lymphocytes Cartilage Cells Chronic Clinical Trials Collagen Collagen Arthritis DBA/1J Mouse Data Dendritic Cells Dendritic cell activation Development Disease Endotoxins Exhibits Experimental Arthritis Fibroblasts Gene Expression Goals Heat shock proteins Human Hyaluronan Immune Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injection of therapeutic agent Innovative Therapy Interleukin-1 Interleukin-10 Interleukin-6 Intervention Joints Knock-out Knockout Mice Knowledge Ligands Lipopolysaccharides Mediating Mitogen-Activated Protein Kinases Modeling Molecular Weight Mus NF-kappa B Pathogenesis Patients Play Production RNA Interference Receptor Activation Receptor Signaling Regulation Rheumatoid Arthritis Role Severity of illness Signal Pathway Signal Transduction Specificity Splenocyte Stimulus System TLR4 gene TNF Receptor-Associated Factors TRAF6 gene Time Tissues Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation Wild Type Mouse arrestin 1 arrestin 2 chemokine clinical practice cytokine healthy volunteer inhibitor/antagonist innovation insight joint destruction knock-down macrophage neutrophil novel novel strategies overexpression research study response

项目摘要

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.

促炎细胞因子和趋化因子在类风湿性关节炎 (RA) 中发挥着关键作用。解决了 Toll 样受体 (TLR) 在 RA 发生和进展中的重要作用。各种 TLR 在关节炎动物模型中的作用已得到证实。透明质酸和热休克蛋白 (HSP)22 等配体在 RA 滑膜组织中高度表达然而，患者与健康供体的比较进一步表明 TLRs 在 RA 发病机制中的作用。 RA 中调节内源性 TLR4 配体诱导的 TLR 激活的途径尚不完全清楚。最近的研究证明了接头蛋白 ¿ -arrestin 1 和 2 与 TRAF6、I¿ B?? ，和 NF??我们的数据首次证明 B1p105 负向调节 TLR 信号传导。 -抑制蛋白2 (KO) 小鼠在胶原抗体诱导的关节炎（CAIA 敲除）模型中表现出更严重的关节炎此外，我们观察到 ¿ -arrestin 1 和 2 表达增加与胶原诱导关节炎 (CIA) 小鼠的脾细胞和成纤维样滑膜细胞 (FLS) 相比还证明LPS-和内源性TLR4配体低分子量。透明质酸 (LMW-HA) 诱导的 TNF¿ ，来自 ¿ 的脾细胞中 IL-6 和 IL-10 的产生增加- 与 WT 小鼠相比，抑制蛋白 2 KO 小鼠的这些发现使我们提出上调的假设。的 -arrestin 1 和 2 表达通过负作用抑制胶原诱导的关节炎中的炎症炎症细胞反应的调节的具体目的是研究 ¿ -arrestin 1 和 2 为 ¿胶原诱导的关节炎中炎症反应的负调节因子。 -arrestin 1 和 2 的表达脾巨噬细胞、CD4+ 和 CD8+ T 淋巴细胞、B 淋巴细胞、树突状细胞 (DC)、多形核白细胞 (PMN) 和 FLS 与小鼠 CIA 模型中疾病严重程度的相关性一旦特定的免疫细胞表现出 ¿ - 鉴定了逮捕蛋白，的角色 ¿ -将使用慢病毒表达检查这些细胞激活时的arrestin 1和2表达系统过度表达 ¿ - 逮捕或击倒 ¿ -RNAi 抑制蛋白。 -抑制素依赖性调节促炎和抗炎基因表达的信号通路将为研究提供新的见解 RA 的发病机制，从中可以发展出创新的有针对性的干预措施。