Intracrine induction of 11beta-hydroxysteroid dehydrogenase type 1 expression by glucocorticoid potentiates prostaglandin production in the human chorionic trophoblast.
Glucocorticoids are involved in the modulation of the release of parturition hormones from the fetal membranes and placenta, where their actions are determined by the prereceptor glucocorticoid metabolizing enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). Two distinct isozymes of 11beta-HSD have been characterized. In the fetal membranes, 11beta-HSD1 is the predominate isozyme; it converts biologically inert 11-ketone glucocorticoid metabolites into active glucocorticoids. Sequence analysis of the cloned 11beta-HSD1 gene revealed a putative glucocorticoid response element in the promoter region. However, whether glucocorticoids modulate 11beta-HSD1 expression in the fetal membranes is unknown. In this study, 11beta-HSD1 and glucocorticoid receptor (GR) were coexpressed in the chorionic trophoblast. Radiometric conversion assay and Northern blot analysis revealed that both 11beta-HSD1 reductase activity and mRNA levels were increased by dexamethasone (1 microM, 0.1 microM) in the cultured chorionic trophoblast, and the effects were blocked by GR antagonist RU486 (1 microM). Prior induction of 11beta-HSD1 by dexamethasone potentiated the subsequent stimulation of prostaglandin H synthetase 2 expression and secretion of prostaglandin E(2) by cortisone in the chorionic trophoblast. There is colocalization of 11beta-HSD1 and GR in the chorionic trophoblast. By binding to GR, glucocorticoids induce the expression of 11beta-HSD1 by a possible intracrine mechanism, thereby amplifying the actions of glucocorticoids on prostaglandin production in the fetal membranes. This cascade of events initiated by glucocorticoids may play an important role in the positive feed-forward mechanisms of labor.
Sun
Kang
K
Department of Physiology, Second Military Medical University, Shanghai 200433, People's Republic of China. sunkang2000@yahoo.com
He
Ping
P
Yang
Kaiping
K
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D002478:Cells, Cultured; D002823:Chorion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003348:Cortisone / Q000494:pharmacology; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D015735:Mifepristone / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D005938:Glucocorticoids; D006727:Hormone Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D003348:Cortisone