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

• 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
• 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

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）：白介素（IL）-17在类风湿关节炎（RA）和关节炎模型的发病机理中已成为关键的炎症细胞因子。产生IL-17的CD4+T细胞最近被鉴定为TH细胞的独特子集并指定为Th17。 Th17子集与幼稚CD4+ T细胞的分化需要在IL-6存在并转化生长因子（TGF）-p的情况下刺激。 IL-23是Th17克隆膨胀所必需的。干扰素（IFN）-y，IL-4，IL-27，IL-25和IL-2负调节Th17的发展。我们在鼠胶原诱导的关节炎（CIA）模型中的初步研究表明，在响应II型胶原蛋白（CLL）免疫时，CIA耐CIA C57BL/6（B6）小鼠表达了高IFN-Y-Y-Y-Y-IL-17和低IL-17，而CIA易感的DBA/1小鼠表达了低IFN-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-Y-IL-IL-17。此外，IFN-y抑制CLL刺激了IL-17的产生。 IFN-Y基因敲除B6小鼠显示出显着增强的IL-17反应，并发展为由IL-17介导的CIA。 Roryt是一种孤儿核激素受体，已与IL-17的主要转录因子有关。我们表明，Roryt的过表达显着增加了CD4+ T细胞的IL-17产生。该提案的目标是定义IFN-Y介导的IL-17抑制的机制，以及在关节炎期间积极调节IL-17产生的因素。我们计划通过关注IFN^Y对Roryt表达的影响并与IL-17基因启动子结合，研究IFN-Y介导的IL-17抑制IL-17的细胞和分子机制低的IFN-Y反应机制。最后，使用Roryt转基因小鼠和CLL TCR转基因小鼠，我们将检查关节炎Th17细胞的发展需要哪些细胞因子以及关节炎的表达和慢性。了解关节炎模型中如何调节关节炎Th17细胞的细节将通过靶向调节IL-17表达的因素为RA中新型治疗设计提供有用的信息。