Positive and Negative Regulation of IL-17 in Experimental Arthritis

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性细胞因子。产生IL-17的CD 4 +T细胞最近已被鉴定为Th细胞的独特亚群并命名为Th 17。从幼稚CD 4 + T细胞分化Th 17亚群需要在IL-6和转化生长因子（TGF）-β存在下的刺激。IL-23是Th 17克隆扩增所需的。干扰素（IFN）-γ、IL-4、IL-27、IL-25和IL-2负调节Th 17发育。我们在鼠胶原诱导的关节炎（CIA）模型中的初步研究显示，响应于II型胶原（C11）免疫，CIA抗性C57 BL/6（B6）小鼠表达高IFN-γ和低IL-17，而CIA易感DBA/1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-γ敲除B6小鼠显示出显著增强的IL-17应答，并发展出由IL-17介导的CIA。ROR γ t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RORyt的过表达显著增加了CD 4 + T细胞的IL-17产生。该建议的目的是确定IFN-γ介导的IL-17抑制的机制和关节炎期间积极调节IL-17产生的因子。我们计划通过重点研究IFN^y对RORyt表达和与IL-17基因启动子结合的影响，研究DBA/1小鼠中低IFN-γ反应的机制以及IFN-γ介导的IL-17抑制的细胞和分子机制。最后，使用ROR γ t转基因小鼠和Cll TCR转基因小鼠，我们将检查致关节炎Th 17细胞的发育和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性Th 17细胞如何调控的细节将为通过靶向调控IL-17表达的因子来设计RA的新治疗方法提供有用的信息。

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.