RANTES/CCL5 mediated tissue remodeling in RA

RANTES/CCL5 介导的 RA 组织重塑

• 批准号: 9269866
• 负责人: Salah-uddin Ahmed
• 金额: $ 3.19万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269866
• 关键词: Acute; Adjuvant Arthritis; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Binding; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cholesterol; Chronic; Comorbidity; Development; Disease; Enzymes; Epigallocatechin Gallate; Extracellular Matrix Degradation; Fibroblasts; Foundations; Gelatinase A; Green tea; Health; Health Care Costs; Hepatic; Hepatotoxicity; Human; IRAK1 gene; In Vitro; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-1; Interleukin-6; Joints; Lead; Link; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Membrane; Osteitis; Patients; Phosphotransferases; Play; Production; Proteins; RANTES; Rattus; Regulation; Rheumatoid Arthritis; Role; Serum; Serum amyloid A protein; Severe Adverse Event; Severities; Signal Transduction; Synovial Cell; Synovitis; TNF gene; TNFSF11 gene; TRANCE protein; Testing; Tissues; Vascular Diseases; Vascular remodeling; Work; arthropathies; base; bone invasion; cadherin-11; conventional therapy; cytokine; disability; efficacy testing; inflammatory marker; inhibitor/antagonist; intravenous administration; joint destruction; joint injury; novel; polyphenol; research study; small molecule inhibitor; socioeconomics; success; therapeutic target; therapy development

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.

描述（由申请人提供）：类风湿性关节炎（RA）是一种关节的慢性炎症性疾病。由高水平的促炎细胞因子，特别是白细胞介素-6 (IL-6) 产生的全身炎症环境，会驱动炎症和滑膜细胞活化，从而导致关节破坏和包括心血管疾病在内的关节外并发症。 IL-6 是一种多效性细胞因子，通过膜结合 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 (MMP-2、-13) 的合成，在滑膜炎症向全身炎症的转变中发挥重要作用。这些蛋白质也会导致 RA 中观察到的血管和关节损伤。唯一针对 IL-6 开发的疗法托珠单抗 (tocilizumab) 已在 RA 治疗中显示出疗效。然而，由于严重的不良事件（例如胆固醇升高和肝毒性）以及与连续静脉给药相关的高昂医疗费用，其使用受到限制。这些问题使得开发用于治疗 RA 的 IL-6 小分子抑制剂变得非常重要。表没食子儿茶素-3-没食子酸酯 (EGCG) 是绿茶中发现的一种有效抗炎多酚，可阻断人 RA 滑膜成纤维细胞 (RA-FLS) 中 IL-1� 诱导的 IL-6 合成。此外，EGCG 显着抑制 IL-1β 诱导的 mgp130 表达，同时作为内源性 IL-6 抑制剂刺激可溶性 gp130 (sgp130) 的产生。在我们的初步研究中，EGCG 预处理抑制了 RA-FLS 中 IL-6/sIL-6R 诱导的 RANKL 和 Cadherin-11 (CAD-11) 的表达。在佐剂诱导性关节炎 (AIA) 大鼠的血清和关节中，IL-6 水平比 IL-1� 或肿瘤坏死因子 (TNF)-� 高几倍，而 EGCG 通过选择性抑制 IL-6 来改善关节炎。在大鼠 AIA 中，观察到 IL-6 驱动的全身 CRP 水平随着关节炎的严重程度达到峰值，表明 IL-6 在促进系统炎症导致 RA 血管功能障碍中发挥重要作用。基于这些新发现，我们将研究 EGCG 抑制关节炎中 IL-6 介导的炎症和骨破坏以及抑制大鼠 AIA 血管功能障碍的机制。这些研究的成功将带来两个重要的临床发现：（1）确定IL-6作为缓解RA血管功能障碍的治疗靶点，（2）EGCG能够抑制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。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。