Dihydrotestosterone inhibits interleukin-1α or tumor necrosis factor α-induced proinflammatory cytokine production via androgen receptor-dependent inhibition of nuclear factor-κB activation in rheumatoid fibroblast-like synovial cell line.
Dihydrotestosterone inhibits interleukin-1α or tumor necrosis factor α-induced proinflammatory cytokine production via androgen receptor-dependent inhibition of nuclear factor-κB activation in rheumatoid fibroblast-like synovial cell line.
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DOI：
10.1248/bpb.34.1724
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发表时间：
2011-11
影响因子：
2
通讯作者：
Jian Xu;Yuka Itoh;H. Hayashi;T. Takii;K. Miyazawa;K. Onozaki
中科院分区：
文献类型：
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作者：
Jian Xu;Yuka Itoh;H. Hayashi;T. Takii;K. Miyazawa;K. Onozaki
类风湿性关节炎（RA）是一种在患病率和临床特征上存在显著性别差异的疾病。滑膜细胞产生的白细胞介素（IL）-1和肿瘤坏死因子（TNF）α是RA的主要炎症介质和破坏介质。我们发现，一种有效的雄激素，5α-二氢睾酮（DHT）抑制IL-1α诱导的RA患者来源的成纤维细胞样滑膜细胞系MH 7A的IL-8，IL-6和IL-1β的产生和mRNA表达。IL-8基因启动子分析表明，核因子（NF）-κB激活是IL-1α激活IL-8基因转录的关键，而DHT以依赖雄激素受体（AR）的方式抑制IL-1α诱导的NF-κB激活。DHT也能抑制TNFα对AR过表达细胞的作用，表明DHT抑制TNFα的作用需要足够的功能性AR表达水平。这些结果表明，雄激素通过以依赖于AR的方式抑制NF-κB活化，抑制IL-1α或TNFα诱导的滑膜成纤维细胞样细胞产生促炎细胞因子，从而有助于预防RA及其性别差异。
Rheumatoid arthritis (RA) is a disease with significant gender differences in its prevalence and clinical features. Interleukin (IL)-1 and tumor necrosis factor (TNF) α produced by synoviocytes are principle inflammatory and destructive mediators of RA. We found that a potent androgen, 5α-dihydrotestosterone (DHT) inhibits IL-1α-induced production and mRNA expression of IL-8, IL-6 and IL-1β from RA patient-derived fibroblast-like synovial cell line MH7A. Promoter analysis of the IL-8 gene revealed that nuclear factor (NF)-κB activation is critical for its transcriptional activation by IL-1α, and DHT inhibited the IL-1α-induced NF-κB activation in a manner dependent on the androgen receptor (AR). DHT also inhibited the effects of TNFα on the cells overexpressed with AR, indicating that sufficient expression level of functional AR was necessary for the inhibitory effect of DHT on TNFα. These results suggest that androgen contributes to the prevention against RA and its gender difference by inhibiting IL-1α or TNFα-induced proinflammatory cytokine production from synovial fibroblast-like cells by inhibiting NF-κB activation in a manner depending on AR.