TRANSCRIPTIONAL REGULATION OF PROSTAGLANDIN-H SYNTHASE-2 GENE IN HUMAN TROPHOBLASTS

Abnormal PG production by placental PG-H synthase (PGHS) is associated with preeclampsia. There are two PGHS isozymes, and their regulation in trophoblasts is presently unknown. We hypothesized that the PGHS is ozymes are differentially regulated in human trophoblasts. To test thi s hypothesis, we transfected primary trophoblasts and JEG3 cells with promoter constructs of either PGHS-1 or PGHS-2 genes. We found that in both cell systems, the basal activity of PGHS-2 promoter was 10- to 3 0-fold higher than the activity of PGHS-1 promoter. In response to eit her 12-0-tetradecanoylphorbol-13-acetate (TPA) or 8-bromo-cAMP, we obs erved an increase in PGHS-2 promoter activity but no change in activit y of PGHS-1 promoter. Similarly, both agents enhanced PGHS-2 expressio n, as well as prostaglandin E-2 production. The activity of PGHS-2 pro moter was potentiated by coexpression of protein kinase A and inhibite d by coexpression of kinase A inhibitor. Aspirin attenuated the stimul atory effect of TPA on PGHS-2 promoter. We conclude that both PGHS-1 a nd PGHS-2 promoters are active in trophoblasts. The activity of PGHS-2 promoter is stimulated by either TPA or cAMP, and the stimulatory eff ect of TPA is attenuated by aspirin. These pathways may play a role in modulation of prostanoid synthesis by trophoblasts.