Cytokine Balance in Rheumatoid Arthritis

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证实，并已被成功的肿瘤坏死因子(TNF)靶向治疗所证实。肿瘤坏死因子是约三分之二对肿瘤坏死因子阻断治疗有反应的类风湿关节炎患者的关键致病因素，也是许多其他自身免疫性/炎症性疾病的关键致病因素。肿瘤坏死因子驱动类风湿关节炎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。肿瘤坏死因子激活细胞并促进急性炎症反应的分子机制已经被广泛研究并被充分理解。令人惊讶的是，人们对慢性暴露于肿瘤坏死因子的影响知之甚少，因为这与类风湿性关节炎的发病机制有关，也不知道肿瘤坏死因子在慢性炎症背景下激活细胞的机制。重要的是要了解慢性肿瘤坏死因子的作用机制，以进一步了解肿瘤坏死因子在慢性炎症中的作用，并发现新的治疗靶点和治疗方法，其基础是抑制对慢性炎症很重要的选择性肿瘤坏死因子功能(从而潜在地保留对宿主防御重要的急性功能)。因此，我们利用原代培养的人单核/巨噬细胞和RA滑膜巨噬细胞进行实验，以探讨慢性肿瘤坏死因子暴露的影响及其潜在的分子机制。我们发现，除了诱导具有良好特征的急性炎症反应外，较长时间的肿瘤坏死因子暴露还会诱导STAT1的高表达和干扰素的应答，并减弱IL-10和IL-27等稳态细胞因子的信号转导。通过观察从RA患者炎症关节临床样本中获得的巨噬细胞中类似的干扰素/STAT1反应以及对IL-10和IL-27的抵抗力，这些发现与人类疾病的相关性得到了验证。我们推测，这些新发现的肿瘤坏死因子功能有助于其促炎特性，并通过减弱体内平衡反应和启动巨噬细胞对STAT1介导的反应而在类风湿关节炎发病机制中发挥作用。此外，我们认为，逆转IL-10和IL-27的耐药性(通过药物增强其信号通路或通过去除耐药诱导物)可能是一种卓有成效的治疗方法。在这一应用中，我们将研究肿瘤坏死因子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滑膜巨噬细胞来最大限度地提高结果与人类RA发病机制的相关性，还将利用肿瘤坏死因子驱动的关节炎和炎症的体内小鼠模型。我们认为，我们的研究将导致对肿瘤坏死因子生物学以及肿瘤坏死因子如何参与类风湿关节炎发病机制的新认识。这些研究将有可能深入了解肿瘤坏死因子的作用机制，这些机制可以作为治疗靶点，同时保留在宿主防御中重要的肿瘤坏死因子的急性功能。 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和治疗靶点。这项应用将探索新的机制，即肿瘤坏死因子通过拮抗体内平衡反应从而增加炎症关节中细胞的激活，从而促进类风湿关节炎的慢性炎症。这些研究可能会对肿瘤坏死因子的作用机制产生新的见解，并可能导致更安全和有效的类风湿关节炎治疗。

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.