Nuclear factor kappaB/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1beta-stimulated synovial fibroblasts.
Nuclear factor kappaB/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1beta-stimulated synovial fibroblasts.
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DOI：
10.1002/1529-0131(199811)41:11
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发表时间：
1998-11
影响因子：
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通讯作者：
M. Vincenti;C. I. Coon;C. Brinckerhoff
中科院分区：
文献类型：
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作者：
M. Vincenti;C. I. Coon;C. Brinckerhoff
目的探讨白细胞介素-1（IL-1）如何通过激活滑膜成纤维细胞胶原酶1（MMP-1）的转录，促进类风湿关节炎软骨的降解。方法用MMP-1启动子/荧光素酶构建体瞬时转染原代兔滑膜成纤维细胞，检测启动子对IL-1的应答活性。一个最小的IL-1反应元件被定义和用于评估DNA结合蛋白的电泳迁移率变动分析和原位紫外交联分析。结果IL-1对兔滑液成纤维细胞MMP-1基因的转录激活需要一个位于核苷酸（nt）-3，029处的背侧样元件以及位于nt-77处的激活蛋白1位点。重要的是，IL-1诱导的DNA结合活性是特异性的背样元件包含核因子κ B（NF-κ B）的p50亚基。结论这些研究首次证明了NF-κ B在诱导MMP-1中的作用，并提出了NF-κ B介导的类风湿性关节炎软骨降解的机制。
OBJECTIVE To determine how interleukin-1 (IL-1), through activation of collagenase 1 (matrix metalloproteinase 1 [MMP-1]) transcription in synovial fibroblasts, contributes to cartilage degradation in rheumatoid arthritis. METHODS Primary rabbit synovial fibroblasts were transiently transfected with MMP-1 promoter/ luciferase constructs, and promoter activity in response to IL-1 was assessed. A minimal IL-1-response element was defined and used to evaluate DNA binding proteins by electrophoretic mobility shift assay and in situ ultraviolet crosslinking assay. RESULTS Transcriptional activation of the MMP-1 gene by IL-1 in rabbit synovial fibroblasts required a dorsal-like element, which was located at nucleotide (nt) -3,029, as well as an activator protein 1 site at nt -77. Importantly, an IL-1-induced DNA binding activity that was specific for the dorsal-like element contained the p50 subunit of nuclear factor kappaB (NF-kappaB). CONCLUSION These studies demonstrate, for the first time, a role for NF-kappaB in the induction of MMP-1, and suggest a mechanism of NF-kappaB-mediated cartilage degradation in rheumatoid arthritis.