Cytokine Balance in Rheumatoid Arthritis

类风湿关节炎中的细胞因子平衡

• 批准号: 7982413
• 负责人: Lionel B Ivashkiv
• 金额: $ 39.43万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982413
• 关键词: Acute; Arthritis; Attenuated; Autoimmune Process; Biology; Cell Adhesion Molecules; Cells; Chondrocytes; Chronic; Clinical; Crohn' s disease; Cytokine Signaling; Disease; Endothelium; Equilibrium; Exposure to; Fibroblasts; Genetic Transcription; Host Defense; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-1; Interleukin-10; Interleukin-6; Joints; Lead; Mediating; Modeling; Molecular; Mus; NF-kappa B; PTPN11 gene; Pathogenesis; Patients; Phosphoric Monoester Hydrolases; Property; Psoriasis; Receptor Inhibition; Recruitment Activity; Resistance; Rheumatoid Arthritis; Role; STAT1 gene; Sampling; Signal Pathway; Signal Transduction; Study models; Synovial Cell; System; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; attenuation; base; chemokine; cytokine; effective therapy; human disease; in vivo; in vivo Model; insight; macrophage; monocyte; new therapeutic target; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): An important role for inflammatory cytokines in rheumatoid arthritis (RA) is well established and has been validated by successful therapeutic targeting of tumor necrosis factor (TNF). TNF is a key pathogenic factor in approximately two thirds of RA patients who are responsive to TNF blockade therapy, and in many additional autoimmune/inflammatory diseases. Mechanisms by which TNF drives RA pathogenesis include activation of synovial cells to produce factors that drive inflammation and tissue destruction. Molecular mechanisms by which TNF acutely activates cells and promotes an acute inflammatory response have been extensively studied and are well understood. Surprisingly little is known about the effects of chronic exposure to TNF, as is relevant for RA pathogenesis, and about mechanisms by which TNF activates cells in the setting of chronic inflammation. It is important to understand mechanisms of chronic TNF action to gain additional insights into the functions of TNF in chronic inflammation and to discover new therapeutic targets and approaches to therapy based on inhibiting selective TNF functions that are important for chronic inflammation (and thus potentially sparing acute functions important for host defense). Therefore, we have initiated experiments using primary human monocytes/macrophages and RA synovial macrophages to explore the effects of chronic TNF exposure and underlying molecular mechanisms. We have found that in addition to inducing a well characterized acute inflammatory response, longer term TNF exposure induces high STAT1 expression and an IFN response, and attenuates signaling by homeostatic cytokines such as IL-10 and IL-27. The human disease relevance of these findings has been validated by observing similar IFN/STAT1 responses and resistance to IL-10 and IL-27 in macrophages obtained from clinical samples obtained from inflamed joints of RA patients. We postulate that these newly discovered TNF functions contribute to its pro-inflammatory properties and role in RA pathogenesis by attenuating homeostatic responses and priming macrophages for STAT1-mediated responses. Furthermore, we propose that reversal of IL-10 and IL-27 resistance (either by pharmacologically augmenting their signaling pathways or by removing inducers of resistance) may represent a fruitful therapeutic approach. In this application, we will investigate mechanisms by which TNF antagonizes homeostatic cytokines, and the functional significance of this inhibition. We will use primary human cells and RA synovial macrophages to maximize the relevance of results for human RA pathogenesis, and will also utilize in vivo murine models of TNF-driven arthritis and inflammation. We propose that our studies will lead to a new view of TNF biology and how TNF can contribute to RA pathogenesis. These studies will potentially yield insights into mechanisms of TNF action that can be therapeutically targeted while preserving acute functions of TNF that are important in host defense. PUBLIC HEALTH RELEVANCE: Tumor necrosis factor (TNF) is an important cytokine in the pathogenesis of rheumatoid arthritis (RA) and a therapeutic target. This application will investigate new mechanisms by which TNF contributes to chronic inflammation in RA by antagonizing homeostatic responses and thereby increasing the activation of cells in inflamed arthritic joints. These studies will potentially yield new insights into mechanisms of TNF action and could lead to safer and effective therapies for RA.

描述（由申请人提供）： 炎症细胞因子在类风湿关节炎（RA）中的重要作用已得到很好的确立，并通过成功的治疗靶向肿瘤坏死因子（TNF）来验证。在大约三分之二的RA患者中，TNF是对TNF封锁治疗以及许多其他自身免疫性/炎症性疾病的关键致病因素。 TNF驱动RA发病机理的机制包括激活滑膜细胞以产生驱动炎症和组织破坏的因素。 TNF急性激活细胞并促进急性炎症反应的分子机制已得到广泛研究并已被充分了解。令人惊讶的是，对于慢性暴露于TNF的影响，与RA发病机理有关，以及TNF在慢性炎症环境中激活细胞的机制知之甚少。重要的是要了解慢性TNF动作的机制，以获得对TNF在慢性炎症中功能的更多见解，并基于抑制选择性的TNF功能，发现对慢性炎症重要的选择性TNF功能（因此对宿主防御重要的急性功能很重要），发现了新的治疗靶标和治疗方法。因此，我们使用原代人单核细胞/巨噬细胞和RA滑膜巨噬细胞开始了实验，以探索慢性TNF暴露和潜在的分子机制的影响。我们发现，除了诱导良好的急性炎症反应外，长期TNF暴露还会诱导高STAT1表达和IFN反应，并通过稳态细胞因子（例如IL-10和IL-27）减弱信号传导。这些发现的人类疾病相关性已通过观察到从RA患者发炎关节获得的临床样本中获得的巨噬细胞中相似的IFN/STAT1反应以及对IL-10和IL-27的耐药性来验证。我们假设这些新发现的TNF功能通过减弱STAT1介导的反应的稳态反应和启动巨噬细胞，从而有助于其促炎的特性和在RA发病机理中的作用。此外，我们建议逆转IL-10和IL-27耐药性（通过药理学来增强其信号通路或消除耐药性诱导者）可能代表富有成果的治疗方法。在此应用中，我们将研究TNF拮抗稳态细胞因子的机制，以及该抑制作用的功能意义。我们将使用原代人细胞和RA滑膜巨噬细胞来最大程度地提高结果与人RA发病机理的相关性，还将利用TNF驱动的关节炎和炎症的体内鼠模型。我们建议我们的研究将导致TNF生物学的新观点以及TNF如何有助于RA发病机理。这些研究可能会产生对TNF作用机制的见解，而TNF作用的机制可以是治疗目标的，同时保留在宿主防御中很重要的TNF的急性功能。 公共卫生相关性： 肿瘤坏死因子（TNF）是类风湿关节炎（RA）和治疗靶标的重要细胞因子。该应用将调查TNF通过拮抗稳态反应，从而增加RA中慢性炎症的新机制，从而增加发炎的关节炎关节中细胞的激活。这些研究可能会产生对TNF作用机制的新见解，并可能导致RA的更安全和有效的疗法。