17β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor α (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERα
17β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor α (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERα
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DOI：
10.4049/jimmunol.178.5.3059
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Onozaki, Kikuo
中科院分区：
文献类型：
--
作者：
Itoh, Yuka;Hayashi, Hidetoshi;Onozaki, Kikuo
风湿性关节炎（RA）发生在女性比男性多四倍，虽然性别差异的机制基础尚不清楚。RA的特征是滑膜细胞过度增殖，产生促炎细胞因子如IL-1。与疾病的发病机制有关。在这项研究中，我们研究了17 β-雌二醇（E2）是否诱导类风湿成纤维细胞样细胞系MH 7A中IL-1 α mRNA的表达，以及RA患者的原代滑膜细胞，并研究了潜在的分子机制。E2以雌激素受体依赖的方式诱导IL-1 α mRNA在两种细胞类型中的表达。在MH 7A细胞中，ER α而不是ER β介导E2的作用。缺失和突变分析显示，IL-1 α基因启动子内的GC丰富区域负责对E2的反应。EMSA显示Sp1和Sp3与富含GC的区域结合，并且Sp1的转录活性通过E2处理而上调。Sp1和ER α相互作用的物理不管E2的存在。还观察到ER α和组蛋白脱乙酰酶2（HDAC 2）之间的物理相互作用，E2诱导HDAC 2从ER α上解离。这些结果表明，E2诱导辅阻遏物HDAC 2从ER α上解离，这导致通过IL-1 α基因启动子内富含GC的区域增强Sp1转录活性。
Rheumatoid arthritis (RA) occurs four times more frequently in women than in men, although the mechanistic basis of the gender difference is unknown. RA is characterized by the overproliferation of synoviocytes producing prointlammatory cytokines such as IL-1. implicated in the pathogenesis of the disease. In this study we examined whether 17 beta-estradiol (E2) induced IL-1 alpha mRNA expression in the rheumatoid fibroblast-like cell line MH7A, as well as in primary synovial cells from RA patients, and investigated the underlying molecular mechanisms. E2 induced IL-1 alpha mRNA expression in both cell types in an estrogen receptor-dependent manner. In MH7A cells ER alpha but not ER beta mediated the effects of E2. Deletion and mutation analysis revealed that a GC-rich region within the IL-1 alpha gene promoter was responsible for the response to E2. EMSAs showed that Sp1 and Sp3 bound to the GC-rich region and that the transcriptional activity of Sp1 was up-regulated by the treatment with E2. Sp1 and ER alpha interacted physically regardless of the presence of E2. Physical interaction was also observed between ER alpha and histone deacetylase 2 (HDAC2), and E2 induced the dissociation of HDAC2 from ER alpha. These results suggest that E2 induces the dissociation of corepressor HDAC2 from ER alpha, which leads to the augmentation of Spl transcriptional activity through the GC-rich region within the IL-1 alpha gene promoter.