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: 6891933
• 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/6891933
• 关键词: AP1 protein; Adenoviridae; cell growth regulation; cell proliferation; clinical research; collagenase; fibroblasts; functional /structural genomics; gene expression; genetic regulation; human tissue; infectious arthritis; 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）：类风湿性关节炎（RA）是一种慢性炎症性和破坏性关节病，导致发病率和死亡率增加。构成滑膜内层（滑膜成纤维细胞）的成纤维细胞是与软骨和骨直接接触的薄膜，是导致 RA 发病机制的主要细胞之一。在 RA 中，滑膜成纤维细胞数量增加并产生促炎细胞因子和基质金属蛋白酶 (MMP)，从而促进炎症和关节破坏。我们最近发现细胞周期抑制剂p21在RA中的一个新作用，即p21不仅能阻断细胞周期进程，还能减少IL-6和MMP-1的合成。与骨关节炎滑膜成纤维细胞相比，RA 中 p21 表达降低。 p21 的恢复可阻断 RA 滑膜成纤维细胞的细胞周期进程并抑制 IL-6 和 MMP-1 合成，但在非 RA 滑膜成纤维细胞中则不然。此外，恢复的 p21 会减弱 AP-1 的 DNA 结合活性，AP-1 是一种在 RA 期间增加的转录因子，也是已知的 IL-6 和 MMP-1 诱导剂。与野生型细胞相比，p21缺陷的滑膜成纤维细胞的IL-6分泌增加了100倍，IL-6和MMP-3 mRNA积累显着增加，并且AP-1 DNA结合活性增强。与 Rb 过表达（也会诱导细胞周期停滞）相反，p21 缺陷滑膜成纤维细胞中 p21 的恢复使 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 途径来抑制正常关节中 IL-6 和 MMP-1 的转录。在 RA 关节中，p21 通路有缺陷，导致滑膜成纤维细胞增殖并增加 IL-6 和 MMP-1 的合成。因此，RA可以通过恢复p21途径来治疗。