RANTES/CCL5 mediated tissue remodeling in RA

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性关节炎症性疾病。由高水平的促炎细胞因子，特别是白介素6(IL-6)产生的全身性炎症环境，驱动炎症和滑膜细胞激活，其特征是关节破坏和关节外并存，包括心血管疾病。IL-6是一种多效性细胞因子，通过膜结合的IL-6受体(IL-6R)和糖蛋白130(Gp130)传递信号。IL-6通过诱导急性反应蛋白(ARP)、RANKL和基质降解酶(MMP2、13)的合成，在滑膜炎症向全身性炎症转化过程中发挥重要作用。这些蛋白也是类风湿关节炎血管和关节损伤的原因之一。针对IL-6开发的唯一疗法tocilizumab在RA治疗中显示出疗效。然而，由于严重的不良事件，如胆固醇升高和肝脏毒性，以及与持续静脉注射相关的高昂医疗成本，它的使用受到限制。这些问题使得开发治疗类风湿关节炎的小分子IL-6抑制剂变得重要。表没食子儿茶素没食子酸酯(EGCG)是绿茶中发现的一种有效的抗炎多酚，可阻断IL-1�诱导人RA滑膜成纤维细胞(RA-FL)合成IL-6。此外，EGCG显著抑制IL-1�诱导的mgp130的表达，同时刺激内源性IL-6抑制物sgp130的产生。在我们的初步研究中，EGCG可抑制IL-6/sIL-6R诱导的RA-FLS中RANKL和CAD-11的表达。佐剂性关节炎大鼠血清和关节中IL-6水平是IL-1�或肿瘤坏死因子-�的数倍，EGCG通过选择性抑制IL-6来改善关节炎。在大鼠AIA模型中，IL-6驱动的全身性C反应蛋白水平随着关节炎的严重程度而达到峰值，提示IL-6在促进类风湿关节炎系统炎症、导致血管功能障碍中起着重要作用。基于这些新的发现，我们将研究EGCG抑制IL-6介导的关节炎炎症和骨破坏以及抑制大鼠AIA血管功能障碍的机制。这些研究的成功将导致两个重要的临床发现：(1)确定IL-6作为治疗靶点以缓解RA的血管功能障碍；(2)EGCG抑制IL-6介导的滑膜和全身炎症以及抑制与RA相关的血管损伤的能力。这项研究的成功完成将为测试EGCG作为RA和其他炎症性疾病的治疗选择奠定基础。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease of the articular joints. A systemic inflammatory milieu generated by high levels of pro-inflammatory cytokines, interleukin-6 (IL-6) in particular, drives the inflammation and synovial cell activation that characterize joint destruction and extra-articular co-morbidities including cardiovascular diseases. IL-6 is a pleiotropic cytokine that transmits its signal via membrane- bound IL-6 receptor (IL-6R) and glycoprotein130 (gp130). IL-6 plays an important role in transition of synovial inflammation into systemic inflammation by inducing the synthesis of acute reactive proteins (ARPs), RANKL, and matrix degrading enzymes (MMP-2, -13). These proteins also contribute to the vascular and joint damage observed in RA. The only therapy developed against IL-6, tocilizumab, has shown efficacy in RA treatment. However, its use is limited due to severe adverse events such as elevated cholesterol and liver toxicity, and the high healthcare costs associated with continuous intravenous administration. These issues make it important to develop small molecule inhibitors of IL-6 for the treatment of RA. Epigallotcatechin-3-gallate (EGCG), a potent anti-inflammatory polyphenol found in green tea, blocks IL-1�-induced IL-6 synthesis in human RA synovial fibroblasts (RA-FLS). Further, EGCG significantly inhibited IL-1�-induced mgp130 expression with concomitant stimulation of soluble gp130 (sgp130) production as an endogenous IL-6 inhibitor. In our preliminary findings, IL-6/sIL-6R-induced expression of RANKL and Cadherin-11 (CAD-11) in RA-FLS was inhibited by EGCG pretreatment. IL-6 levels are several-fold higher than those of IL-1� or tumor necrosis factor (TNF)-� in the serum and joints of adjuvant-induced arthritis (AIA) rats, and EGCG ameliorated arthritis via selective inhibition of IL-6. IL-6 driven systemic CRP levels were observed to peak with the severity of arthritis in rat AIA suggesting an important role of IL-6 in promoting systemi inflammation leading to vascular dysfunction in RA. Based on these novel findings, we will study the mechanisms through which EGCG inhibits IL-6 mediated inflammation and bone destruction in arthritis and suppresses vascular dysfunction in rat AIA. The success of these studies will lead to two clinically important findings: (1) The identification of IL-6 as a therapeutic target t alleviate vascular dysfunction in RA, and (2) EGCG's ability to suppress IL-6 mediated synovial and systemic inflammation and to inhibit vascular damage associated with RA. Successful completion of this study will lay the foundation for testing EGCG as a treatment option for RA and other inflammatory diseases.