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Analysis of transcriptional factors which are responsible for the expression of inflammatory cytokines in rheumatoid arthritis synovial cells.

分析负责类风湿性关节炎滑膜细胞中炎症细胞因子表达的转录因子。

基本信息

批准号：
07807053
负责人：
ETO Sumiya
金额：
$ 1.34万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

1. IL-1 upregulated IL-1 and IL-6 mRNA expression in synovial cells. In Rheumatoid Arthritis (RA) synovial cells, these mRNA were expressed more rapidly after IL-1 stimulation compared with that in synovial cells from patients with osteoarthritis. It suggested preexsiting transcriptional factors were activated immediately after the stimulation without de novo synthesis of transcrptional factors in RA synovial cells.2. Besides the stimulation by soluble factors like IL-1, synovial cells were also stimulated through the cellular adhesion. Either the cell adhesion with PMA pretreated T cells or the crosslinking of ICAM-1 molecules on synovial cells resulted in the induction of IL-1 mRNA expression.3. Then we have established synovial fibroblastic cell line E11 from a patient with RA and analyzed the transcriptional regulation of inflammatory cytokines using CAT and band shift assays. Both the addition of IL-1 and crosslinking of ICAM-1 molecules on the surface of E11 resulted in the upregulation of CAT activitiese of the enhancer region located at the sequences between -3134 and -2729bp upstream of transcriptional initiation site of IL-1beta gene.4. AP-1 binding site in this region was indispensable for the induction of CAT activitiese by the stimulation. Furthermore, activation of AP-1 protein after stimulation by IL-1 or crosslinking of ICAM-1 was comfirmed by bandshift assay.These results suggest that activation of AP-1 protein stimulated by soulble factors and cell adhesion play an important role in the pathological upregulation of inflammatory cytokines in RA synovial cells. Inhibition of activation of AP-1 might be a new therapeutic strategy to control the progression of RA.

1.IL-1上调滑膜细胞IL-1和IL-6mRNA的表达。在类风湿性关节炎(RA)滑膜细胞中，IL-1刺激后这些mRNA的表达速度比骨关节炎患者滑膜细胞中的表达更快。提示RA滑膜细胞在刺激后即刻激活存在前转录因子，而不重新合成转录因子。滑膜细胞除受到IL-1等可溶性因子的刺激外，还可通过细胞黏附刺激滑膜细胞。无论是细胞与PMA处理过的T细胞的黏附，还是滑膜细胞表面ICAM-1分子的交联性，均可诱导IL-1mRNA的表达。然后，我们建立了一个RA患者的滑膜成纤维细胞系E11，并用CAT和条带移位分析了炎性细胞因子的转录调控。IL-1的加入和ICAM-1分子在E11表面的交联均导致位于IL-1β基因转录起始点上游-3134~-2729bp之间的增强子区CAT活性上调。AP-1在该区域的结合部位是刺激诱导CAT活性所必需的。此外，通过带移分析证实了IL-1刺激或ICAM-1交联后AP-1蛋白的激活，这一结果表明，在RA滑膜细胞炎性细胞因子的病理性上调中，由可溶性因子刺激的AP-1蛋白的激活和细胞黏附在病理上起着重要作用。抑制AP-1的激活可能是控制RA进展的新的治疗策略。