Differential regulation of 11beta-hydroxysteroid dehydrogenase type-1 and -2 gene transcription by proinflammatory cytokines in vascular smooth muscle cells.
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.
Tsugita
Makoto
M
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan.
Iwasaki
Yasumasa
Y
Nishiyama
Mitsuru
M
Taguchi
Takafumi
T
Shinahara
Masayuki
M
Taniguchi
Yoshinori
Y
Kambayashi
Machiko
M
Terada
Yoshio
Y
Hashimoto
Kozo
K
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D018808:Transcription Factor AP-1 / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D008156:Luciferases