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Peroxisome Proliferator-Activated Receptor Suppresses 11ß-Hydroxysteroid Dehydrogenase Type 2 Gene Expression in Human Placental Trophoblast Cells

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

Address all correspondence and requests for reprints to: Dr. K. Yang, Children’s 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.

Accumulating evidence suggests that the human placental enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) plays a key role in fetal development by controlling fetal exposure to maternal glucocorticoids. Recently, the nuclear peroxisome proliferator-activated receptor (PPAR) has been found to be the most abundantly expressed PPAR subtype in the human placenta, but its function in this organ is unknown. Given that PPAR-null mice exhibited placental defects and consequent intrauterine growth restriction, the present study was undertaken to examine the hypothesis that PPAR regulates human placental function in part by targeting 11ß-HSD2. Using cultured human trophoblast cells as a model system, we demonstrated that 1) the putative PPAR agonist carbaprostacyclin (cPGI₂) reduced 11ß-HSD2 activity as well as 11ß-HSD2 expression at both protein and mRNA levels; 2) GW610742 (a selective PPAR agonist) mimicked the effect of cPGI₂, whereas indomethacin (a known ligand for PPAR and PPAR) had no effect; 3) the cPGI₂-induced down-regulation of 11ß-HSD2 mRNA did not require de novo protein synthesis; 4) cPGI₂ suppressed HSD11B2 promoter activity, but did not alter the half-life of 11ß-HSD2 mRNA; and 5) the inhibitory effect of cPGI₂ on HSD11B2 promoter activity was abrogated in trophoblast cells cotransfected with a dominant negative PPAR mutant. Taken together, these findings suggest that activation of PPAR down-regulates HSD11B2 gene expression in human trophoblast cells, and that this effect is mediated primarily at the transcriptional level. Thus, the present study reveals 11ß-HSD2 as an additional target for PPAR and identifies a molecular mechanism by which this nuclear receptor may regulate human placental function.

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