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（由适用提供）：类风湿关节炎（RA）是关节关节的慢性炎症性疾病。高水平的促炎细胞因子（尤其是白介素-6（IL-6））产生的全身性炎症环境驱动感染和滑膜细胞激活，这些感染和滑膜细胞激活表征关节疾病和关节外的核心疾病，包括心血管疾病。 IL-6是一种多效细胞因子，通过膜结合的IL-6受体（IL-6R）和糖蛋白蛋白130（GP130）传输其信号。 IL-6通过诱导急性反应性蛋白（ARP），RANKL和基质降解酶（MMP-2，-13）的合成，在滑膜注射向全身注射中的过渡中起重要作用。这些蛋白质还有助于RA中观察到的血管和关节损伤。针对IL-6 Tocilizumab开发的唯一疗法已显示出RA治疗的效率。但是，由于严重的不良事件（例如胆固醇和肝毒性）以及与连续静脉内给药相关的高医疗费用，因此其使用受到限制。这些问题使开发IL-6的小分子抑制剂以治疗RA变得重要。 Epigallotcatechin-3-Gallate（EGCG）是一种在绿茶中发现的潜在抗炎多酚，阻止了人RA滑膜成纤维细胞（RA-FLS）中IL-1诱导的IL-6合成。此外，EGCG显着抑制了IL-1诱导的MGP130表达，并刺激了固体GP130（SGP130）作为内源性IL-6抑制剂的固体GP130（SGP130）产生。在我们的初步发现中，EGCG预处理抑制了IL-6/SIL-6R诱导的Ra-FLS中RANKL和CADHERIN-11（CAD-11）（CAD-11）的表达。 IL-6水平比IL-1或肿瘤坏死因子（TNF）高几倍。观察到IL-6驱动的全身性CRP水平与大鼠AIA的关节炎严重程度达到峰值，这表明IL-6在促进Systemi炎症中的重要作用，导致RA的血管功能障碍。基于这些新的发现，我们将研究EGCG抑制关节炎中IL-6介导的滑膜和骨破坏的机制，并抑制大鼠AIA的血管功能障碍。这些研究的成功将导致两个临床上重要的发现：（1）将IL-6鉴定为RA中的治疗靶标T减轻了血管功能障碍，以及（2）EGCG抑制IL-6介导的突发型和全身感染并抑制与RA相关的血管损伤的能力。这项研究的成功完成将为EGCG作为RA和其他炎症性疾病的治疗选择奠定基础。