Role of PGE2 in CNS and peripheral autoimmune disorders

描述（由申请人提供）：对自身抗原的致病性th1型免疫反应被认为在许多器官特异性自身免疫性疾病中起重要作用。然而，最近在多发性硬化症、克罗恩病和类风湿性关节炎动物模型中的进展表明，产生IL-17的T细胞（ThlL-17）而不是产生ifng的Th1细胞是自身免疫的最相关参与者。活化的抗原呈递细胞（ARC）通过释放IL-12p70控制Th1效应物的产生，通过IL- 23控制ThlL-17的产生。与大多数既能诱导IL-23又能诱导IL-12的ARC激活剂不同，我们发现PGE2是IL-23的诱导剂，而IL-12p70的作用则被削弱。本研究的核心假设是炎症条件下释放的PGE2促进IL-23的表达和产生，同时减少树突状细胞和小胶质细胞中IL-12p70的释放，诱导ThlL-17的产生和/或增殖。我们提出，通过IL-23- > - IL-17轴，PGE2有助于维持受影响组织中的自身免疫易发环境。在Specific Aim 1中，我们建议对暴露于PGE2或在PGE2存在下生成的树突状细胞（DC）和小胶质细胞（MG）进行IL-23/IL-12生成的表征，并评估它们在体外和体内生成ThlL-17细胞的能力。Specific Aim 2主要关注PGE2在DC中诱导的信号通路，以及PGE2调控p19、p40和p35基因转录的相关信号分子和转录因子的鉴定。在Specific Aim 3中，我们建议通过评估临床症状、相关组织病理学、产生IL-17的T细胞的发育以及受影响组织和外周淋巴器官中的细胞因子谱，来评估PGE2在体内两种自身免疫性疾病模型（胶原诱导的关节炎和实验性自身免疫性脑脊髓炎）中的作用。识别参与产生il -23的APC和致病性ThlL-17的产生、激活和维持的分子和细胞因子将对我们对自身免疫性疾病的理解和干预产生重大影响。阐明PGE2控制IL-23/IL-12平衡的分子机制，鉴定dc和小胶质细胞上PGE2受体的功能，是开发新的自身免疫治疗途径的最终目标。

DESCRIPTION (provided by applicant): Pathogenic Th1-type immune responses to self-antigens are thought to play an essential role in a number of organ-specific autoimmune diseases. However, recent developments in animal models of multiple sclerosis, Crohn's disease, and rheumatoid arthritis, suggest that IL-17 producing T cells (ThlL-17) rather than the IFNg-producing Th1 cells are the most relevant participants in autoimmunity. Activated antigen-presenting cells (ARC) control the development of Th1 effectors through IL-12p70 release, and of ThlL-17 through IL- 23. In contrast to most ARC activators that induce both IL-23 and IL-12, we identified PGE2 as an inducer of IL-23 at the expense of IL-12p70. The central hypothesis in this proposal is that PGE2 released in inflammatory conditions promotes the expression and production of IL-23, while reducing IL-12p70 release from dendritic cells and microglia, and induces the subsequent generation and/or proliferation of ThlL-17. We propose that, through the IL-23-->IL-17 axis, PGE2 contributes to the maintenance of an autoimmune-prone environment in the affected tissues. In Specific Aim 1 we propose to characterize dendritic cells (DC) and microglia (MG) exposed to or generated in the presence of PGE2 in terms of IL-23/IL-12 production and to assess their in vitro and in vivo capacity to generate ThlL-17 cells. Specific Aim 2 is focused on the PGE2- induced signaling in DC and the identification of the relevant signaling molecules and transcription factors involved in the PGE2 regulation of p19, p40, and p35 gene transcription. In Specific Aim 3 we propose to evaluate the role of PGE2 in vivo in two models of autoimmune diseases, the collagen-induced arthritis and the experimental autoimmune encephalomyelitis by assessing clinical symptoms, the relevant histopathology, the development of IL-17 producing T cells, and the cytokine profile in the affected tissues and in the peripheral lymphoid organs. The identification of the molecular and cellular factors involved in the generation, activation, and maintenance of IL-23-producing APC and of pathogenic ThlL-17 will have a significant impact on our understanding and intervention in autoimmune diseases. The ultimate goal for the clarification of the molecular mechanisms involved in the PGE2 control of the IL-23/IL-12 balance and for the identification of the functional PGE2 receptors on DCs and microglia is the development of new therapeutic avenues in autoimmunity.