Regulation of IL-6 mediated inflammation and tissue destruction by EGCG

EGCG 对 IL-6 介导的炎症和组织破坏的调节

基本信息

批准号：
8636996
负责人：
Salah-uddin Ahmed
金额：
$ 32.09万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636996
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 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 Rattus Regulation Rheumatoid Arthritis Role Serum Serum amyloid A protein Severe Adverse Event Severities Signal Transduction Synovial Cell TNFSF11 gene TRANCE protein Testing Tissues Tumor Necrosis Factor-alpha Vascular Diseases Vascular remodeling Work arthropathies base bone invasion cadherin-11 conventional therapy cytokine disability efficacy testing gallocatechol human IRAK1 protein inflammatory marker inhibitor/antagonist intravenous administration joint destruction joint injury novel polyphenol public health relevance research study small molecule socioeconomics success therapeutic target therapy development

项目摘要

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驱动炎症。 IL-6 是一种多效性细胞因子，通过膜结合 IL-6 受体传递信号。 (IL-6R) 和糖蛋白 130 (gp130) 通过诱导急性反应蛋白 (ARP)、RANKL 和基质降解酶 (MMP-2) 的合成，在滑膜炎症向全身炎症的转变中发挥重要作用。 13). 这些蛋白质也会导致 RA 中观察到的血管和关节损伤。由于严重的不良事件（例如胆固醇升高和肝毒性）以及与持续静脉注射相关的高医疗成本，开发用于治疗 RA 的 IL-6 小分子抑制剂非常重要。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-FLS) 中的 IL-6 合成此外，EGCG 显着抑制 IL-1¿ - 诱导 mgp130 表达，同时刺激可溶性 gp130 (sgp130) 作为内源性 IL-6 抑制剂的产生。在我们的初步发现中，IL-6/sIL-6R 诱导 RA 中 RANKL 和钙粘蛋白-11 (CAD-11) 的表达。 -FLS 被 EGCG 预处理抑制，IL-6 水平比 IL-1 高几倍。或肿瘤坏死因子 (TNF)-¿在佐剂诱导性关节炎 (AIA) 大鼠的血清和关节中，观察到 EGCG 通过选择性抑制 IL-6 驱动的全身 CRP 水平达到峰值，表明大鼠 AIA 中关节炎的严重程度具有重要意义。 IL-6 在促进 RA 血管功能障碍的系统炎症中的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并抑制大鼠血管功能障碍的机制。 AIA。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，以及（2）EGCG 抑制 IL-6 介导的滑膜和全身的能力。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。