Cytokine Balance in Rheumatoid Arthritis

描述（由申请人提供）： 炎性细胞因子在类风湿关节炎（RA）中的重要作用已得到充分证实，并已通过肿瘤坏死因子（TNF）的成功治疗靶向得到验证。TNF是对TNF阻断治疗有反应的约三分之二RA患者以及许多其他自身免疫性/炎性疾病的关键致病因素。TNF驱动RA发病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子。 TNF急性激活细胞和促进急性炎症反应的分子机制已被广泛研究和充分理解。令人惊讶的是，关于长期暴露于TNF的影响（与RA发病机制相关）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作用的机制，以获得对TNF在慢性炎症中的功能的额外见解，并发现新的治疗靶点和基于抑制对慢性炎症重要的选择性TNF功能的治疗方法（并因此潜在地保留对宿主防御重要的急性功能）。因此，我们已经启动了使用原代人单核细胞/巨噬细胞和RA滑膜巨噬细胞的实验，以探索慢性TNF暴露的影响和潜在的分子机制。我们已经发现，除了诱导充分表征的急性炎症反应之外，较长期的TNF暴露诱导高STAT 1表达和IFN反应，并减弱通过稳态细胞因子如IL-10和IL-27的信号传导。这些发现的人类疾病相关性已经通过观察从RA患者的发炎关节获得的临床样品中获得的巨噬细胞中类似的IFN/STAT 1应答和对IL-10和IL-27的抗性来验证。我们推测，这些新发现的TNF功能有助于其促炎特性和RA发病机制中的作用，通过减弱稳态反应和启动巨噬细胞的STAT 1介导的反应。此外，我们提出逆转IL-10和IL-27抗性（通过增强其信号传导途径或通过去除抗性诱导物）可能代表一种富有成效的治疗方法。在本申请中，我们将研究TNF拮抗稳态细胞因子的机制，以及这种抑制的功能意义。我们将使用原代人类细胞和RA滑膜巨噬细胞，以最大限度地提高人类RA发病机制的结果的相关性，也将利用TNF驱动的关节炎和炎症的体内小鼠模型。我们建议，我们的研究将导致一个新的观点TNF生物学和TNF如何有助于RA的发病机制。这些研究将可能深入了解TNF作用机制，这些机制可以在治疗上靶向，同时保留TNF在宿主防御中重要的急性功能。 公共卫生相关性： 肿瘤坏死因子（TNF）是类风湿关节炎（RA）发病机制中的重要细胞因子，也是治疗RA的靶点。本申请将研究TNF通过拮抗稳态反应从而增加发炎关节中细胞的活化而促进RA慢性炎症的新机制。这些研究可能会对TNF的作用机制产生新的见解，并可能导致更安全和有效的RA治疗。

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.