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 11β-hydroxysteroid dehydrogenase (11β-HSD). Two distinct isozymes of 11β-HSD have been characterized. In the fetal membranes, 11β-HSD1 is the predominate isozyme; it converts biologically inert 11-ketone glucocorticoid metabolites into active glucocorticoids. Sequence analysis of the cloned 11β-HSD1 gene revealed a putative glucocorticoid response element in the promoter region. However, whether glucocorticoids modulate 11β-HSD1 expression in the fetal membranes is unknown. In this study, 11β-HSD1 and glucocorticoid receptor (GR) were coexpressed in the chorionic trophoblast. Radiometric conversion assay and Northern blot analysis revealed that both 11β-HSD1 reductase activity and mRNA levels were increased by dexamethasone (1 μM, 0.1 μM) in the cultured chorionic trophoblast, and the effects were blocked by GR antagonist RU486 (1 μM). Prior induction of 11β-HSD1 by dexamethasone potentiated the subsequent stimulation of prostaglandin H synthetase 2 expression and secretion of prostaglandin E2 by cortisone in the chorionic trophoblast. There is colocalization of 11β-HSD1 and GR in the chorionic trophoblast. By binding to GR, glucocorticoids induce the expression of 11β-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.
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