p21-Mediated Regulation of IL-6 and MMP-1 in RA

RA 中 p21 介导的 IL-6 和 MMP-1 调节

• 批准号: 6675459
• 负责人: Harris R Perlman
• 金额: $ 28.52万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675459
• 关键词: AP1 protein; Adenoviridae; cell growth regulation; cell proliferation; clinical research; collagenase; fibroblasts; functional /structural genomics; gene expression; genetic regulation; human tissue; interleukin 6; joints; laboratory mouse; oncoprotein p21; protein structure function; rheumatoid arthritis; transfection /expression vector; yeast two hybrid system

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy that results in increased morbidity and mortality. The fibroblasts that comprise the synovial lining (synovial fibroblasts), a thin membrane in direct contact with cartilage and bone, are one of the principal cells responsible for the pathogenesis of RA. In RA, the synovial fibroblasts increase in number and produce pro-inflammatory cytokines and matrix-metalloproteinases (MMPs) that promote inflammation and joint destruction. We recently discovered a novel role for the cell cycle inhibitor p21 in RA, namely that p21 not only blocks cell cycle progression, it also reduces the synthesis of IL-6 and MMP-1. p21 expression is reduced in RA compared to osteoarthritis synovial fibroblasts. Restoration of p21 blocks cell cycle progression and suppresses IL-6 and MMP-1 synthesis in RA but not in non-RA synovial fibroblasts. Additionally, restored p21 attenuates the DNA binding activity of AP-1, a transcription factor that is increased during RA and is a known inducer of IL-6 and MMP-1. p21-deficient synovial flbroblasts exhibit a 100-fold increase in IL-6 secretion, a marked increase in IL-6 and MMP-3 mRNA accumulation, and enhanced AP-1 DNA binding activity compared to wild-type cells. In contrast to Rb overexpression, which also induces cell cycle arrest, restoration of p21 in p21-deficient synovial fibroblasts returned IL-6 and MMP-3 to wild-type levels. Based on our data, we hypothesize that p21 suppresses IL-6 and MMP-1 transcription in the normal joint through the inhibition of the AP-1 pathway. In the RA joint, the p21 pathway is defective, resulting in proliferation of synovial fibroblasts and increased synthesis of IL-6 and MMP-1. Accordingly, RA may be treatable by restoring the p21 pathway.

描述（由申请人提供）：类风湿关节炎（RA）是一种慢性炎症性和破坏性关节炎，导致发病率和死亡率增加。包含滑膜衬里的成纤维细胞（滑膜成纤维细胞）是一种直接与软骨和骨骼接触的薄膜，是负责RA发病机理的主要细胞之一。在RA中，滑膜成纤维细胞的数量增加，并产生促炎和关节破坏的促炎性细胞因子和基质 - 绝素蛋白酶（MMP）。最近，我们在RA中发现了细胞周期抑制剂P21的新作用，即p21不仅可以阻止细胞周期进程，还降低了IL-6和MMP-1的合成。与骨关节炎滑膜成纤维细胞相比，RA的p21表达降低。 p21的恢复会阻止细胞周期的进程并抑制RA中的IL-6和MMP-1合成，但在非RA滑膜成纤维细胞中却不能。此外，恢复的p21减弱了AP-1的DNA结合活性，AP-1的转录因子在RA期间增加，并且是IL-6和MMP-1的已知诱导剂。 P21缺陷型滑素细胞表现出IL-6分泌的100倍，与野生型细胞相比，IL-6和MMP-3 mRNA积累的显着增加以及AP-1 DNA结合活性增强。与RB过表达相反，RB的过表达也诱导细胞周期停滞，P21缺陷型滑膜成纤维细胞中P21的恢复返回IL-6和MMP-3恢复到野生型水平。根据我们的数据，我们假设p21通过抑制AP-1途径抑制正常关节中的IL-6和MMP-1转录。在RA关节中，p21途径有缺陷，导致滑膜成纤维细胞增殖并增加IL-6和MMP-1的合成。因此，可以通过恢复P21途径来治疗RA。