Differential regulation of 11β-hydroxysteroid dehydrogenase type-1 and -2 gene transcription by proinflammatory cytokines in vascular smooth muscle cells

Glucocorticoid hormone is activated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) mainly in glucocorticoid-target organs such as the liver and the anterior corticotroph cells, and inactivated by type 2 (11β-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 11β-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 11β-HSD-1 was stimulated by a representative proinflammatory cytokine TNFα, 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 11β-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 11β-HSD-2. The increase and decrease in 11β-HSD-1 and 11β-HSD-2 expression during inflammatory stimuli, respectively, were expected to cause the enhancement in glucocorticoid action, which was confirmed by the fact that TNFα 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 11β-HSD-1 and 11β-HSD-2.