title: Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by progesterone, estrogen, and the cyclic adenosine 5'-monophosphate pathway in cultured human placental and chorionic trophoblasts.
abstract: Human placenta and fetal membranes contain two types of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). 11Beta-HSD1 interconverts cortisol and cortisone and is the predominant isoform found in the fetal membranes. 11Beta-HSD2, which predominates in the placenta syncytiotrophoblast, converts cortisol to cortisone. It has been proposed that placental 11beta-HSD protects the fetus from high levels of maternal glucocorticoids. In this study, cultured term human placental and chorionic trophoblasts were used to examine the regulation of 11beta-HSD1 and 11beta-HSD2 activities and mRNA expression by progesterone, estrogen, and activators of adenylate cyclase (forskolin) and protein kinase C (phorbol 12-myristate 13-acetate, PMA). Placental trophoblast displayed mainly type 2 oxidase activities. 11Beta-HSD in the chorionic trophoblast was exclusively an 11beta-HSD1 reductase. Progesterone (0.001-1 microM) inhibited 11beta-HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enhanced 11beta-HSD2 activity. The inhibitory effect of progesterone on 11beta-HSD2 activity was not reversed by the progesterone receptor antagonists RU-486 or onapristone. Progesterone (1 microM) also reduced levels of 11beta-HSD2 mRNA, an effect that was attenuated by both RU-486 and onapristone. Estradiol (1 microM) inhibited type 2 oxidase activity as well. Activation of adenylate cyclase by forskolin (100 microM) up-regulated both 11beta-HSD2 activity and mRNA expression; there was no effect of PMA (1 microM) on 11beta-HSD2. 11Beta-HSD1 reductase activity was unaffected by progesterone, estrogen, forskolin, or PMA in either the placental or chorionic trophoblasts. We conclude that both progesterone and estrogen are inhibitors of 11beta-HSD2 activity in term human placenta in vitro. Levels of 11beta-HSD2 activity and mRNA are increased by activation of the cAMP pathway. Progesterone also suppresses levels of 11beta-HSD2 mRNA.
authors.affiliation: MRC Group in Fetal and Neonatal Health and Development, Department of Physiology, University of Toronto, Ontario, Canada. kang.sun@utoronto.ca
authors.forename: K
authors.initials: K
authors.lastname: Sun
authors.forename: K
authors.initials: K
authors.lastname: Yang
authors.forename: J R
authors.initials: JR
authors.lastname: Challis
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D002478:Cells, Cultured; D002823:Chorion / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D005576:Colforsin; D011374:Progesterone; D004958:Estradiol; D000242:Cyclic AMP; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D013755:Tetradecanoylphorbol Acetate