Dihydrotestosterone decreases tumor necrosis factor-α and lipopolysaccharide-induced inflammatory response in human endothelial cells
Dihydrotestosterone decreases tumor necrosis factor-α and lipopolysaccharide-induced inflammatory response in human endothelial cells
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DOI：
10.1210/jc.2005-1664
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发表时间：
2006-02-01
影响因子：
5.8
通讯作者：
Catapano, AL
中科院分区：
文献类型：
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作者：
Norata, GD;Tibolla, G;Catapano, AL
背景：越来越多的证据表明，睾酮可能对动脉粥样硬化的发展产生有益的影响。有人建议，睾酮可能会采取行动后，转化为雌二醇和激活雌激素受体，然而，直接作用的雄激素对血管壁已经proposed.Objective：我们调查的影响，双氢睾酮对促炎症反应中观察到的人内皮细胞。设计：在存在或不存在二氢睾酮（DHT）的情况下，将从脐带分离的人内皮细胞与脂多糖或TNF α孵育。mRNA和细胞蛋白被处理用于基因表达研究，瞬时转染实验被用来研究所观察到的效应的分子机制。设置：这些研究在米兰大学药理科学系进行，米兰，意大利。结果：脂多糖和TNF α诱导VCAM-1和ICAM-1 mRNA和蛋白表达，如通过实时定量PCR，荧光激活细胞分选，和共聚焦显微镜，但这种影响被抑制时，细胞与DHT孵育。此外，DHT抑制IL-6、MCP-1、CD 40、TLR 4、派-1和考克斯-2的mRNA表达以及细胞因子和趋化因子如GRO、粒细胞-巨噬细胞集落刺激因子和TNF的释放。雄激素受体拮抗剂比卡鲁胺可以抵消双氢睾酮的作用。此外，当细胞共转染考克斯-2启动子或3X-NF-κ B荧光素酶报告载体和表达人雄激素受体的质粒时，DHT处理抑制TNF α观察到的荧光素酶活性的增加。结论：DHT可以通过控制内皮细胞中核因子-κ B介导的炎症反应来积极调节内皮功能。
Context: An increasing body of evidence suggests that testosterone may exert beneficial effects on the development of atherosclerosis. It was suggested that testosterone may act after conversion into estradiol and activation of the estrogen receptors; however, a direct role of androgens on the vascular wall has been proposed.Objective: We investigated the effects of dihydrotestosterone on the proinflammatory response observed in human endothelial cells.Design: Human endothelial cells isolated from umbilical cords were incubated with lipopolysaccharide or TNF alpha in the presence or absence of dihydrotestosterone (DHT). mRNA and cellular proteins were processed for gene expression studies, and transient transfection experiments were performed to investigate molecular mechanisms involved in the effects observed.Setting: These studies took place at the Department of Pharmacological Sciences, University of Milan, Milan, Italy.Results: Lipopolysaccharide and TNF alpha induced VCAM-1 and ICAM-1 mRNA and protein expression, as detected by real-time quantitative PCR, fluorescence-activated cell sorting, and confocal microscopy, but this effect was inhibited when cells were incubated with DHT. In addition, DHT inhibited mRNA expression of IL-6, MCP-1, CD40, TLR4, PAI-1, and Cox-2 and the release of cytokines and chemokines such as GRO, granulocyte-macrophage colony-stimulating factor, and TNF. The DHT effect was counteracted by bicalutamide, an antagonist of the androgen receptor. Furthermore, when cells were cotransfected with a Cox-2 promoter or a 3X-NF-kappa B luciferase reporter vector and a plasmid expressing the human androgen receptor, DHT treatment inhibited the increase of the luciferase activity observed with TNF alpha.Conclusion: DHT could positively regulate endothelial function through the control of the inflammatory response mediated by nuclear factor-kappa B in endothelial cells.