New Therapy for Rheumatoid Arthritis with Cell Cycle Regulators

细胞周期调节剂治疗类风湿关节炎的新疗法

基本信息

批准号：
12557048
负责人：
KOHSAKA Hitoshi
金额：
$ 8.51万
依托单位：
Tokyo Medical & Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557048/
关键词：
rheumatoid arthritis cell cycle gene therapy 慢性関節リウマチ

项目摘要

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.

滑膜组织中细胞周期蛋白依赖性激酶抑制剂（CDKI）基因，PL6INKA和P21CIPL的强迫表达有效地治疗类风湿关节炎的动物模型（RA）。抑制了处理的关节中的滑膜增生，反映了p16inka和p21Cipl对细胞周期进程的抑制作用。另外，抑制了淋巴细胞浸润，炎性细胞因子的表达以及骨骼和软骨的破坏。为了辨别细胞周期调节基因如何执行这种完整效应，我们通过或不带有P21基因的类风湿滑膜滑膜成纤维细胞研究了基因表达。 DNA阵列和随后的常规分析表明，各种炎症介质和组织降解蛋白酶的下调，这些蛋白酶与RA的病理非常重要。这些分子包括IL-6，-8，I型IL-1受体（IL-1R1），单核细胞化学吸引蛋白-1，巨噬细胞炎性蛋白-3α，组织蛋白酶B和K，MMP-1和-3。 P21Cipl对IL-1R1的下调实际上导致对IL-1的反应性减弱。即使没有IL-1，也可以看到p21对炎症基因表达的抑制。这种IL-1R1独立的抑制使NF-KB和激活蛋白-1转录因子失活。这些多重作用可以有助于抑制细胞循环，以改善关节炎，并表明CDKIS与免疫效应分子之间存在意外关系。