Positive and Negative Regulation of IL-17 in Experimental Arthritis

IL-17 在实验性关节炎中的正向和负向调节

基本信息

批准号：
7470800
负责人：
CONG-QIU CHU
金额：
$ 1.15万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470800
关键词：
Acute Antigens Arthritis Autoantigens Autoimmune Process Binding CD4 Positive T Lymphocytes Cell Proliferation Cells Chronic Classification Clonal Expansion Collagen Arthritis Collagen Type II DBA/1 Mouse Defect Development Epigenetic Process Experimental Arthritis Gene Expression Regulation Genes Goals Helper-Inducer T-Lymphocyte Immunization Inflammation Inflammatory Interferons Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-6 Interleukins Knock-out Lead Mediating Modeling Molecular Mouse Strains Mus Nuclear Hormone Receptors Orphan Pathogenesis Predisposition Production Protein Overexpression Regulation Resistance Rheumatoid Arthritis Secondary to Signal Transduction Stimulus T-Cell Receptor T-Lymphocyte Testing Transforming Growth Factors Transgenic Mice Transgenic Organisms cytokine design in vivo interleukin-23 microbial novel therapeutics promoter response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Interleukin (IL)-17 has emerged to be a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA) and arthritis models. CD4+T cells producing IL-17 has recently been identified as a distinct subset of Th cells and designated Th17. The differentiation of Th17 subset from naive CD4+ T cells requires stimulation in the presence of IL-6 and transforming growth factor (TGF)-p. IL-23 is required for Th17 clonal expansion. Interferon (IFN)-y, IL-4, IL-27, IL-25 and IL-2 negatively regulate Th17 development. Our preliminary studies in murine collagen-induced arthritis (CIA) model showed that in response to collagen type II (Cll) immunization, CIA resistant C57BL/6 (B6) mice expressed high IFN-y and low IL-17 while CIA susceptible DBA/1 mice expressed low IFN-y and high IL-17. Moreover, IFN-y suppressed Cll stimulated IL-17 production. IFN-y knockout B6 mice displayed significantly enhanced IL-17 response and developed CIA that was mediated by IL-17. RORyt is an orphan nuclear hormone receptor that has been implicated as master transcription factor for IL-17. We showed that overexpression of RORyt markedly increased IL-17 production by CD4+ T cells. The goals of this proposal are to define the mechanisms of IFN-y mediated suppression of IL-17 and factors positively regulate IL-17 production during arthritis. We plan to investigate the mechanisms for low IFN-y response in DBA/1 mice and cellular and molecular mechanisms of IFN-y mediated suppression of IL-17 by focusing on effects of IFN^y on RORyt expression and binding to IL-17 gene promoter. Finally, using RORyt transgenic mice and Cll TCR transgenic mice we will examine what cytokines are required for development of arthritogenic Th17 cells and arthritis expression and chronicity. Understanding the details of how arthritogenic Th17 cells are regulated during arthritis models will provide useful information for novel therapeutic design in RA by targeting factors regulating IL-17 expression.

描述（由申请人提供）：白细胞介素（IL）-17已成为类风湿性关节炎（RA）和关节炎模型发病机制中的关键炎症细胞因子。产生 IL-17 的 CD4+T 细胞最近被确定为 Th 细胞的一个独特亚群，并命名为 Th17。 Th17 亚群从初始 CD4+ T 细胞的分化需要在 IL-6 和转化生长因子 (TGF)-p 存在的情况下进行刺激。 Th17 克隆扩增需要 IL-23。干扰素 (IFN)-y、IL-4、IL-27、IL-25 和 IL-2 负向调节 Th17 发育。我们对小鼠胶原诱导关节炎 (CIA) 模型的初步研究表明，响应 II 型胶原 (Cll) 免疫，CIA 抗性 C57BL/6 (B6) 小鼠表达高 IFN-y 和低 IL-17，而 CIA 易感 DBA/ 1只小鼠表达低IFN-γ和高IL-17。此外，IFN-γ抑制Cll刺激的IL-17产生。 IFN-y 敲除 B6 小鼠表现出显着增强的 IL-17 反应，并发展出由 IL-17 介导的 CIA。 RORyt 是一种孤儿核激素受体，被认为是 IL-17 的主转录因子。我们发现 RORyt 的过表达显着增加了 CD4+ T 细胞的 IL-17 产量。该提案的目标是确定 IFN-γ 介导的 IL-17 抑制机制以及关节炎期间积极调节 IL-17 产生的因子。我们计划通过重点关注 IFN^y 对 RORyt 表达和与 IL-17 基因结合的影响，研究 DBA/1 小鼠中低 IFN-y 反应的机制以及 IFN-y 介导的 IL-17 抑制的细胞和分子机制。发起人。最后，使用 RORyt 转基因小鼠和 Cll TCR 转基因小鼠，我们将检查致关节炎 Th17 细胞发育以及关节炎表达和慢性化所需的细胞因子。了解关节炎模型中致关节炎 Th17 细胞如何受到调节的细节将为通过靶向调节 IL-17 表达的因子来设计 RA 的新型治疗设计提供有用的信息。