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：
7911699
负责人：
Hongkuan Fan
金额：
$ 7.38万
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：
2009
资助国家：
美国
起止时间：
2009-08-11 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911699
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 public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): 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 2-arrestin 1 and 2 associating with TRAF6, I:B1, and NF:B1p105 negatively regulate TLR signaling. Our data demonstrated for the first time that 2-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 2-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 TNF1, IL-6 and IL-10 production were augmented in splenocytes from 2- arrestin 2 KO mice compared to WT mice. These findings led us to propose the hypothesis that up-regulation of 2-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 2-arrestin 1 and 2 as negative regulators of the inflammatory response in collagen-induced arthritis. 2-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 2-arrestins are identified, the role of 2-arrestin 1 and 2 expression on activation of these cells will be examined using the lentiviral expression system to overexpress 2-arrestins or knock down 2-arrestins with RNAi. Understanding 2-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. PUBLIC HEALTH RELEVANCE: This project investigates the role of 2-arrestin 1 and 2 as negative regulators of inflammatory response in collagen-induced arthritis. Understanding 2-arrestin 1 and 2 expression in correlation to the disease severity and its cellular specificity in the collagen-induced arthritis model in mice and role of 2-arrestin 1 and 2 expression on endogenous Toll-like receptor ligands and other stimuli induced inflammatory response will provide novel insights into the pathogenesis of rheumatoid arthritis from which innovative targeted interventions can evolve.

描述（由申请人提供）：促炎性细胞因子和趋化因子在类风湿关节炎（RA）中起关键作用。最近的研究已经解决了Toll样受体（TLR）在RA的发展和进展中的作用。已经证明了各种TLR在关节炎动物模型中的重要作用。 TLR4和内源性TLR4配体（例如透明质酸和热休克蛋白（HSP）22）在RA患者的滑膜组织中高度表达，与健康供体相比，与健康供体有关RA发病机理中的健康供体进一步暗示TLR。但是，尚不完全了解调节内源性TLR4配体诱导的TLR激活的信号通路。最近的研究表明，与TRAF6，I：B1和NF：B1P105相关的衔接蛋白2- art蛋白1和2辅助蛋白对TLR信号传导负面调节。我们的数据首次证明，与野生型（WT）小鼠相比，在胶原蛋白抗体诱导的关节炎（CAIA）模型中，2-arrestin 2敲除（KO）小鼠在胶原蛋白诱导的关节炎（CAIA）模型中表现出更严重的关节炎。此外，我们观察到与对照小鼠相比，脾细胞和成纤维细胞样的滑膜细胞（CIA）小鼠中的2-甲蛋白1和2表达增加。还证明了LPS-和内源性TLR4配体低分子量透明质酸（LMW-HA） - 与WT小鼠相比，在2-抑制蛋白2 KO小鼠的脾细胞中增加了诱导的TNF1，IL-6和IL-10的产生。这些发现使我们提出了这样一个假设，即2-甲蛋白1和2表达的上调通过负调节炎症细胞反应来抑制胶原蛋白诱导的关节炎的炎症。具体的目的是研究2-次素1和2作为在胶原蛋白引起的关节炎中炎症反应的负调节剂的作用。脾巨噬细胞，CD4+和CD8+ T淋巴细胞，B淋巴细胞，树突状细胞（DC）S，多形核核白细胞（PMN）S和FLS与小鼠CIA模型中疾病疾病的相关性相关性。一旦确定了表现出改变2-次蛋白表达的特定免疫细胞，将使用慢病毒表达系统对2-次蛋白1和2表达在激活这些细胞的激活中的作用过表达2-次列蛋白或用RNAI击倒2- prestins。了解调节促疾病和抗炎基因表达的2-辅助依赖性信号通路将为RA的发病机理提供新颖的见解，而RA的发病机理可以从中发展出创新的靶向干预措施。公共卫生相关性：该项目调查了2-次素1和2作为炎症反应的负调节剂在胶原蛋白引起的关节炎中的作用。了解与疾病验证的相关性及其在胶原蛋白诱导的关节炎模型中的相关性及其细胞特异性中的2-次蛋白1和2的表达，以及2- art蛋白1和2表达在内源性TOLL样受体配体和其他刺激的炎症反应上的作用，将为射传中射出的Neckumation Intervation Insovity Animake evertions Insovity Insove Insoveliations Insevent severiations Insovelions Insovelions Insovelions Insighations Insover insove Insights。