Tissue specific effects of thyroid hormone on 11β-hydroxysteroid dehydrogenase gene expression

Abstract

11β-Hydroxysteroid dehydrogenase (11β-HSD) by converting active glucocorticoid to an inactive metabolite confers specificity upon the mineralocorticoid receptor (MR) and regulates ligand access to the glucocorticoid receptor (GR). Factors which influence 11β-HSD activity seem likely to be of considerable importance in the modulation of both mineralocorticoid and glucocorticoid hormone action. The administration of tri-iodothyronine (T 3) to rats has previously been shown to reduce 11β-HSD activity in liver but not in kidney. We have studied the effect of T 3 on 11β-HSD gene expression in vivo in rat liver, kidney, distal colon and pituitary. In addition the effects of T 3 on 11β-HSD gene expression in vitro in the rat pituitary GH 3 cell line have been studied. T 3 administration to normal adult rats (40 μg/day, s.c. for 1, 3 and 7 days) resulted in a marked decline in liver and pituitary 11β-HSD mRNA levels and activity following 3 and 7 days of treatment. These reduced levels were maintained for 3 days following withdrawal of T 3 treatment, but returned to control levels after 7 days. In contrast 11β-HSD mRNA and activity in kidney and distal colon were unaffected by T 3 treatment at each time point studied. In vitro, levels of 11β-HSD mRNA and activity in GH 3 cells were unchanged following 8, 24 and 72 h treatment with T 3 (10 −8 to 10 −6M). T 3 bio-activity was confirmed by a marked dose-dependent decline in the expression of the T 3 and glucocorticoid responsive gene, prolactine. T 3 inhibits 11β-HSD gene expression in both liver and pituitary at a pre-translational level. This effect is absent in the predominantly mineralocorticoid target tissues, kidney and distal colon, i.e. it is tissue specific and as such is consistent with the existence of multiple differentially regulated isoforms of 11β-HSD. The time course of the T 3 effect in liver and pituitary in vivo and the lack of any effect in vitro suggests that this action is indirect, and not as a result of interaction between the T 3 receptor and the putative thyroid hormone response element on the rat 11β-HSD gene.