Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis
Gene transfer of a cell cycle modulator exerts anti-inflammatory effects in the treatment of arthritis
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DOI：
10.4049/jimmunol.171.9.4913
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发表时间：
2003-11-01
影响因子：
4.4
通讯作者：
Miyasaka, N
中科院分区：
文献类型：
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作者：
Nonomura, Y;Kohsaka, H;Miyasaka, N
在滑膜组织中强制表达周期蛋白依赖性激酶抑制剂基因p21（Cip1）对类风湿关节炎动物模型有效。治疗后关节滑膜增生受到抑制，反映了p21（Cip1）对细胞周期进展的抑制作用。此外，淋巴细胞浸润、炎症细胞因子的表达以及骨和软骨的破坏均受到抑制。为了确定为什么细胞周期调节基因具有这种抗炎作用，我们研究了p21（Cip1）基因转移或不转移的类风湿性滑膜成纤维细胞的基因表达。我们发现p21（Cip1）基因转移下调了各种炎症介质和组织降解蛋白酶的表达，这些炎症介质和组织降解蛋白酶在类风湿关节炎的病理中起着关键作用。这些分子包括IL-6、-8、I型IL-1R （IL-1R1）、单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-3、组织蛋白酶B和K、基质金属蛋白酶-1和-3。p21（Cip1）下调IL-1R1导致对IL-1的反应性减弱。即使IL-1缺失，p21（Cip1）也能抑制炎症基因的表达。这种与il - 1r1无关的抑制伴随着与p21（Cip1）相关的c-Jun n末端激酶活性降低，以及NF-kappaB和AP-1的失活。这些多重调节作用应该与抑制细胞周期改善关节炎的主要作用一致，并表明迄今为止尚未探索的周期蛋白依赖性激酶抑制剂基因与炎症分子之间的关系。
Forced expression of a cyclin-dependent kinase inhibitor gene, p21(Cip1) in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21(Cip1) on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21(Cip1) gene transferred. We have found that p21(Cip1) gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3alpha, cathepsins B and K, and matrix metalloproteinases-1 and -3. Downregulation of IL-1R1 by p21(Cip1) resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21(Cip1) was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21(Cip1), and inactivation of NF-kappaB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.