New Therapy for Rheumatoid Arthritis with Cell Cycle Regulators

在滑膜组织中强制表达细胞周期蛋白依赖性激酶抑制剂（CDKI）基因p16 INKa和p21 Cipl对治疗类风湿性关节炎（RA）动物模型是有效的。在治疗关节滑膜增生被抑制，反映了p16 INKa和p21 Cipl对细胞周期进程的抑制作用。此外，淋巴细胞浸润，炎性细胞因子的表达，以及骨和软骨的破坏受到抑制。为了辨别细胞周期调节基因如何发挥这种互补作用，我们研究了有或没有p21基因转移的类风湿性滑膜成纤维细胞的基因表达。DNA阵列和随后的常规分析已经证明了各种炎症介质和组织降解蛋白酶的下调，这些炎症介质和组织降解蛋白酶在RA的病理学中至关重要。这些分子包括IL-6、IL-8、I型IL-1受体（IL-1 R1）、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白-3 α、组织蛋白酶B和K、MMP-1和MMP-3。p21 Cipl下调IL-1 R1实际上导致对IL-1的反应性减弱。即使在IL-1不存在的情况下，也可以看到p21对炎症基因表达的抑制。这种IL-1 R1非依赖性抑制伴随着NF-κ B和激活蛋白-1转录因子的失活。这些多重作用可有助于抑制细胞周期以改善关节炎，并提示CDKI和免疫效应分子之间迄今未探索的关系。

Forced expression of a cyclin-dependent kinase inhibitor (CDKI) gene, pl6INKa and p21Cipl in the synovial tissues was effective in treating animal models of rheumatoid arthritis (RA). Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p16INKa and p21Cipl on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To discern how the cell cycle regulator gene exerted such complementary effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21 gene transferred. DNA array and subsequent conventional analyzes have demonstrated downregulation of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of RA. These molecules included IL-6, -8, type I IL-1 receptor (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, MMP-1 and -3. Downregulation of IL-1R1 by p21Cipl actually resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21 was seen even when IL-1 is absent. This IL-1R1-independent suppression accompanied inactivation of NF-kB and activator protein-1 transcription factors. These multiple effects could assist inhibition of cell cycling in ameliorating the arthritis, and suggest a heretofore unexplored relationship between CDKIs and immunological effector molecules.