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Glucocorticoids Stimulate the Expression of 11ß-Hydroxysteroid Dehydrogenase Type 2 in Cultured Human Placental Trophoblast Cells

Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Child Health Research Institute, and Lawson Health Research Institute, Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 4G5

Address all correspondence and requests for reprints to: Dr. K. Yang, Child Health Research Institute, Room A5-132, Victoria Research Laboratories, Westminster Campus, 800 Commissioners Road East, London, Ontario, Canada N6A 4G5. E-mail: kyang{at}uwo.ca.

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

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