Glucocorticoids stimulate the expression of 11beta-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells.
Proper glucocorticoid exposure in utero is vital for normal fetal organ growth and maturation. The placental enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), plays a pivotal role in controlling fetal exposure to high levels of maternal glucocorticoid by converting cortisol into its inactive metabolite, cortisone. The present study was designed to determine whether glucocorticoids auto-regulate 11beta-HSD2 in the human placenta using cultured trophoblast cells as a model system. Trophoblasts were isolated from uncomplicated term placentas and treated with glucocorticoids. The synthetic glucocorticoid dexamethasone increased 11beta-HSD2 activity in a time- and concentration-dependent manner; this effect was accompanied by a corresponding increase in 11beta-HSD2 mRNA. Furthermore, the glucocorticoid receptor antagonist, RU-486, abrogated the dexamethasone-induced increase in 11beta-HSD2 activity, suggesting that the effect of dexamethasone is mediated through the glucocorticoid receptor. Results from transient transfection and mRNA decay experiments indicate that the glucocorticoid-induced increase in 11beta-HSD2 expression is mediated at both the transcriptional and posttranscriptional levels. In conclusion, the present study demonstrates that in cultured human trophoblasts, 11beta-HSD2 is subject to auto-regulation by glucocorticoids. If this occurs in the human placenta in vivo, the glucocorticoid-induced up-regulation of placental 11beta-HSD2 would represent an important safeguard mechanism by which the fetus may be protected from detrimental exposure to elevated levels of maternal glucocorticoids.
van Beek
Jonathan P
JP
Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Child Health Research Institute, London, Ontario, Canada N6A 4G5.
Guan
Haiyan
H
Julan
Laura
L
Yang
Kaiping
K
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis / Q000737:chemistry; D011965:Receptors, Glucocorticoid / Q000235:genetics; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000201:enzymology*
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2