Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG

EGCG 抑制 CCR1/CCR5 介导的血管生成和关节破坏

• 批准号: 7646209
• 负责人: Salah-uddin Ahmed
• 金额: $ 0.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646209
• 关键词: Adjuvant Arthritis; Adoptive Transfer; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Autoimmune Diseases; CCR1 gene; Cartilage; Cells; Chemokine (C-C Motif) Receptor 5; Chemotaxis; Chimera organism; Chronic; Dermal; Development; Dinoprostone; Enzymes; Epigallocatechin Gallate; Fibroblasts; Foundations; Gelatinase A; Green tea; Human; Implant; Incidence; Inflammatory; Inhibition of Matrix Metalloproteinases Pathway; Interleukin-12; Interleukin-6; Interleukins; Joints; Lead; Macrophage Inflammatory Proteins; Matrix Metalloproteinase Inhibitor; Mediating; Methods; Modeling; Mononuclear; Nature; Onset of illness; Production; Proteins; Rattus; Regulation; Rheumatoid Arthritis; SCID Mice; Severe Combined Immunodeficiency; Severities; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tissue Grafts; Tissues; Treatment Protocols; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Work; analog; angiogenesis; arthropathies; articular cartilage; bone; chemokine; conventional therapy; cyclooxygenase 2; disability; efficacy testing; gallocatechol; health economics; in vivo; joint destruction; macrophage; monocyte; novel; novel therapeutics; prevent; receptor expression; research study; success

DESCRIPTION (provided by applicant): PROJECT SUMMARY Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which activated synovial fibroblasts produce chemokines that facilitate the invasion of the articular cartilage and underlying bone by the release of matrix-degrading enzymes. Importantly, RANTES/CCL5 and macrophage inflammatory protein (MIP-11)/CCL3 are the chemokines shown to activate CCR1 and CCR5 receptor to attract T cells and monocytes into joints during the onset of disease. Thus, regulation of CCR1/CCR5 receptor expression is emerging as a novel therapeutic strategy for RA. In our preliminary findings, epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory molecule, blocked interleukin-12 (IL-12)-induced RANTES/CCL5 and MIP-11/CCL3 ) production in RA synovial fibroblasts that are mediated via CCR1/CCR5 receptors. EGCG also inhibited IL-12-induced markers of cartilage and bone destruction (IL-6, VEGF, and PGE2), and matrix degrading enzyme matrix metalloproteinase-2 (MMP-2) activity in human RA synovial fibroblasts. [An in vivo study showed that EGCG prevented adjuvant-induced arthritis (AIA) in rats.] This proposal capitalizes on these novel observations. The central hypothesis of the work proposed is that EGCG inhibits cell recruitment, angiogenesis and joint destruction in rat adjuvant-induced arthritis (AIA) model and in RA synovial tissue (ST)-severe combined immunodeficient (SCID) chimera by blocking CCR1/CCR5 receptor expression. In Aim 1, we will test whether EGCG inhibits CCR1/CCR5 receptor expression to suppress RANTES/CCL5 or MIP-11/CCL3 activity and angiogenesis in RA ST explants. In Aim 2, we will study if EGCG blocks CCR1/CCR5 receptor mediated cell recruitment and tissue invasion in a human RA ST- severe combined immunodeficiency (SCID) mouse chimera. Finally, in Aim 3, we will determine whether EGCG downregulates CCR1/CCR5 receptor expression to inhibit angiogenesis, and cartilage and bone destruction in a rat AIA model of RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potential treatment option for RA and possibly other autoimmune diseases. PROJECT NARRATIVE Rheumatoid arthritis (RA), a chronic inflammatory joint disorder, is a leading cause of work-related disabilities and a significant socio-economic health challenge due to expensive, yet incomplete, conventional therapies. Using animal models of human RA, we propose to test the efficacy of epigallocatechin-3-gallate (EGCG), a potential anti-inflammatory molecule found in green tea, in inhibiting the destruction of the cartilage and bone in RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potentially safe and inexpensive treatment option for RA.

描述（由申请人提供）： 风湿性关节炎（RA）是一种慢性炎症性关节疾病，其中活化的滑膜成纤维细胞产生趋化因子，通过释放基质降解酶促进关节软骨和底层骨的侵袭。重要的是，RANTES/CCL 5和巨噬细胞炎性蛋白（MIP-11）/CCL 3是显示激活CCR 1和CCR 5受体以在疾病发作期间吸引T细胞和单核细胞进入关节的趋化因子。因此，调节CCR 1/CCR 5受体表达成为RA的一种新的治疗策略。在我们的初步研究中，表没食子儿茶素-3-没食子酸酯（EGCG），一种有效的抗炎分子，阻断了RA滑膜成纤维细胞中由CCR 1/CCR 5受体介导的白细胞介素-12（IL-12）诱导的RANTES/CCL 5和MIP-11/CCL 3）的产生。EGCG还抑制IL-12诱导的软骨和骨破坏的标志物（IL-6、VEGF和PGE 2），以及人RA滑膜成纤维细胞中基质降解酶基质金属蛋白酶-2（MMP-2）的活性。[An体内研究表明，EGCG可预防大鼠的佐剂性关节炎（AIA）。]这项建议利用了这些新的观察结果。这项工作的中心假设是，EGCG通过阻断CCR 1/CCR 5受体的表达，抑制大鼠关节炎（AIA）模型和RA滑膜组织（ST）-严重联合免疫缺陷（SCID）嵌合体中的细胞募集、血管生成和关节破坏。在目标1中，我们将测试EGCG是否抑制CCR 1/CCR 5受体表达以抑制RANTES/CCL 5或MIP-11/CCL 3活性和RA ST外植体中的血管生成。在目标2中，我们将研究EGCG是否阻断人RA ST-严重联合免疫缺陷（SCID）嵌合体小鼠中CCR 1/CCR 5受体介导的细胞募集和组织侵袭。最后，在目标3中，我们将确定在RA的大鼠AIA模型中，EGCG是否下调CCR 1/CCR 5受体表达以抑制血管生成、软骨和骨破坏。所提出的实验的成功可能导致EGCG作为RA和可能的其他自身免疫性疾病的潜在治疗选择的发展的重大进展。风湿性关节炎（RA）是一种慢性炎症性关节疾病，是导致工作相关残疾的主要原因，也是一个重大的社会经济健康挑战，因为传统疗法昂贵但不完整。使用人类类风湿关节炎的动物模型，我们建议测试表没食子儿茶素-3-没食子酸酯（EGCG），一个潜在的抗炎分子发现在绿色茶，在抑制类风湿关节炎的软骨和骨的破坏的功效。所提出的实验的成功可能会导致EGCG作为一种潜在的安全和廉价的RA治疗选择的发展取得重大进展。