Glucocorticoids stimulate the expression of 11β-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells

Abstract

Proper glucocorticoid exposure in utero is vital for normal fetal organ growth and maturation. The placental enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSB2), 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 11β-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 11β-HSB2 activity in a time- and concentration-dependent manner; this effect was accompanied by a corresponding increase in 11β-HSD2 mRNA. Furthermore, the glucocorticoid receptor antagonist, RU-486, abrogated the dexamethasone-induced increase in 11β-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 11β-HSB2 expression is mediated at both the transcriptional and posttranscriptional levels. In conclusion, the present study demonstrates that in cultured human trophoblasts, 11β-HSD2 is subject to auto-regulation by glucocorticoids. If this occurs in the human placenta in vivo, the glucocorticoid-induced up-regulation of placental 11β-HSD2 would represent an important safeguard mechanism by which the fetus may be protected from detrimental exposure to elevated levels of maternal glucocorticoids.