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