首页> 外文期刊>Life sciences >Differential regulation of 11beta-hydroxysteroid dehydrogenase type-1 and -2 gene transcription by proinflammatory cytokines in vascular smooth muscle cells.
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Differential regulation of 11beta-hydroxysteroid dehydrogenase type-1 and -2 gene transcription by proinflammatory cytokines in vascular smooth muscle cells.

机译:血管平滑肌细胞中促炎性细胞因子对11β-羟类固醇脱氢酶1型和-2基因转录的差异调节。

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摘要

Glucocorticoid hormone is activated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) mainly in glucocorticoid-target organs such as the liver and the anterior corticotroph cells, and inactivated by type 2 (11beta-HSD-2) in mineralocorticoid-target cells such as renal and colonic epithelial cells. In this study, we examined the expression and action of these glucocorticoid-metabolizing enzymes in the A10 rat aortic smooth muscle cells (VSMC) in vitro. We found that both 11beta-HSD-1 and -2 mRNAs as well as glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were expressed in the cells. Interestingly, the transcriptional activity of 11beta-HSD-1 was stimulated by a representative proinflammatory cytokine TNFalpha, and inflammation-related inducible transcription factors AP1 and C/EBPs might have been at least partly responsible for the effect. In contrast, the transcriptional activity of 11beta-HSD-2 was decreased during the same stimuli, and another inflammation-induced transcription factor Egr-1 might have mediated the effect by interfering with the effect of Sp1, which maintains the basal expression of 11beta-HSD-2. The increase and decrease in 11beta-HSD-1 and 11beta-HSD-2 expression during inflammatory stimuli, respectively, were expected to cause the enhancement in glucocorticoid action, which was confirmed by the fact that TNFalpha elicited the cortisone-to-cortisol conversion using our bioassay system which employs the glucocorticoid-responsive reporter gene. Altogether, our results strongly suggest that inflammatory stress facilitates the intracellular glucocorticoid activation, i.e. conversion from inactive cortisone to active cortisol, by modifying the expression of both 11beta-HSD-1 and 11beta-HSD-2.
机译:糖皮质激素激素主要由糖皮质激素靶器官(例如肝脏和前皮质营养细胞)中的11beta-羟类固醇脱氢酶1型(11beta-HSD-1)激活,而在盐皮质激素靶中的2型(11beta-HSD-2)失活。细胞,例如肾和结肠上皮细胞。在这项研究中,我们检查了这些糖皮质激素代谢酶在A10大鼠主动脉平滑肌细胞(VSMC)中的表达和作用。我们发现11beta-HSD-1和-2 mRNAs以及糖皮质激素受体(GR)和盐皮质激素受体(MR)在细胞中表达。有趣的是,11beta-HSD-1的转录活性受到代表性的促炎性细胞因子TNFalpha的刺激,而炎症相关的诱导型转录因子AP1和C / EBP可能至少部分负责了这种作用。相反,在相同刺激下11beta-HSD-2的转录活性降低,另一种炎症诱导的转录因子Egr-1可能通过干扰Sp1的作用来介导该作用,Sp1维持了11beta-HSD-2的基础表达。 HSD-2。预计炎症刺激期间11beta-HSD-1和11beta-HSD-2表达的增加和减少分别引起糖皮质激素作用的增强,这一事实已被以下事实所证实:TNFα引发了使用我们的生物测定系统采用了糖皮质激素反应型报告基因。总而言之,我们的结果强烈表明,炎症应激通过修饰11β-HSD-1和11β-HSD-2的表达,促进了细胞内糖皮质激素的活化,即从无活性的可的松转化为活性的皮质醇。

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