Role of PGE2 in CNS and peripheral autoimmune disorders

PGE2 在中枢神经系统和外周自身免疫性疾病中的作用

• 批准号: 7883705
• 负责人: Doina Ganea
• 金额: $ 1.74万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883705
• 关键词: Adenylate Cyclase; Affect; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Applications Grants; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Brain; CCL22 gene; CCL3 gene; CCL4 gene; CD4 Positive T Lymphocytes; CXCL10 gene; Cells; Chemotactic Factors; Clinical; Collagen Arthritis; Crohn' s disease; Cyclic AMP; Dendritic Cells; Development; Dinoprostone; Down-Regulation; Environment; Equilibrium; Experimental Autoimmune Encephalomyelitis; Figs - dietary; Funding; Gene Expression; Generations; Genetic Transcription; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Histopathology; Human; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Interleukin-12; Interleukin-17; Interleukin-6; Intervention; Ligands; Lymphoid; Maintenance; Mediator of activation protein; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Neuropeptides; Organ; Parkinson Disease; Participant; Peripheral; Play; Production; Progress Reports; Publications; Rattus; Regulation; Reporting; Resistance; Rest; Rheumatoid Arthritis; Role; Signal Transduction; Signaling Molecule; Stab Wounds; Symptoms; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFSF5 gene; Testing; Th1 Cells; Th1/Th2 Differentiation Pathway; Tissues; Toll-like receptors; United States National Institutes of Health; Up-Regulation; Vasoactive Intestinal Peptide; chemokine; cytokine; graft vs host reaction; in vivo; interleukin-23; leukemia; macrophage; novel therapeutics; pituitary adenylate cyclase activating polypeptide; prevent; receptor; research study; resistant strain; transcription factor

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.

描述（由申请人提供）：对自身抗原的致病性Th 1型免疫应答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，多发性硬化症、克罗恩病和类风湿性关节炎的动物模型的最新进展表明，产生IL-17的T细胞（ThIL-17）而不是产生IFN-γ的Th 1细胞是自身免疫中最相关的参与者。活化的抗原呈递细胞（ARC）通过IL-12 p70释放控制Th 1效应物的发展，并通过IL- 23控制Th 1 L-17的发展。与诱导IL-23和IL-12的大多数ARC激活剂相反，我们鉴定PGE 2作为IL-23的诱导剂，其代价是IL-12 p70。该提议中的中心假设是在炎性条件下释放的PGE 2促进IL-23的表达和产生，同时减少IL-12 p70从树突细胞和小胶质细胞的释放，并诱导随后的ThIL-17的产生和/或增殖。我们认为，通过IL-23-->IL-17轴，PGE 2有助于维持受影响组织中的自身免疫倾向环境。在具体目标1中，我们提出了在IL-23/IL-12产生方面表征暴露于PGE 2或在PGE 2存在下产生的树突状细胞（DC）和小胶质细胞（MG），并评估它们在体外和体内产生ThIL-17细胞的能力。具体目标2集中于PGE 2诱导的DC信号传导和鉴定参与PGE 2调节p19、p40和p35基因转录的相关信号传导分子和转录因子。在具体目标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细胞的发展以及受影响组织和外周淋巴器官中的细胞因子谱来评估PGE 2在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）中的体内作用。参与产生IL-23的APC和致病性ThIL-17的产生、激活和维持的分子和细胞因子的鉴定将对我们理解和干预自身免疫性疾病具有显著影响。澄清参与PGE 2控制IL-23/IL-12平衡的分子机制以及鉴定DC和小胶质细胞上的功能性PGE 2受体的最终目标是开发自身免疫的新治疗途径。