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细胞最近被确认为Th细胞的一个独特的亚群，并命名为Th17。从初始的CD4+T细胞分化为Th17亚群需要在IL-6和转化生长因子-β的刺激下进行。Th17的克隆性扩增需要IL-23。干扰素-γ、IL-4、IL-27、IL-25和IL-2负向调节Th17的发育。我们在胶原性关节炎(CIA)小鼠模型上的初步研究表明，对于II型胶原(CLL)免疫，CIA耐药的C57BL/6(B6)小鼠表达高的干扰素-γ和低的IL-17，而对CIA敏感的DBA/1小鼠则表达低的干扰素-γ和高的IL-17。此外，干扰素-γ还能抑制CLL刺激的IL-17的产生。干扰素-γ基因敲除的B6小鼠表现出显著增强的IL-17反应，并产生由IL-17介导的CIA。RORyt是一种孤儿核激素受体，被认为是IL-17的主要转录因子。我们发现过表达RORyt显著增加了CD4+T细胞产生IL-17。这项建议的目的是明确干扰素-γ介导的抑制IL-17的机制，以及在关节炎过程中正向调节IL-17产生的因素。我们计划通过研究干扰素对小鼠RORyt表达和与IL-17基因启动子结合的影响，来探讨DBA/1小鼠低干扰素反应的机制，以及干扰素-γ抑制IL-17的细胞和分子机制。最后，使用RORyt转基因小鼠和CLL TCR转基因小鼠，我们将检查哪些细胞因子是导致关节炎的Th17细胞发展和关节炎表达和慢性化所必需的。了解致关节炎Th17细胞在关节炎模型中的调控细节，将通过靶向调节IL-17表达的因子为RA的新治疗设计提供有用的信息。