Peroxisome proliferator-activated receptor-gamma modulates differentiationof human trophoblast in a ligand-specific manner

The ligand-dependent nuclear receptor peroxisome proliferator-activated rec eptor-gamma (PPAR gamma) regulates the differentiation of several tissues a nd cell types. PPAR gamma was recently determined to be essential for murin e placental development and differentiation. We therefore assessed the infl uence of PPAR gamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPA R gamma expression and found that PPAR gamma is present in syncytiotrophobl asts and cytotrophoblasts in placental villi. We correlated the expression of PPAR gamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimula tes PPAR gamma activity, but has no effect on PPAR gamma expression. We dem onstrated that the PPAR gamma ligand 15-deoxy-Delta(12,14)-prostaglandin J( 2) (15 Delta PGJ(2)) and the thiazolidinedione troglitazone stimulate PPAR gamma activity in the trophoblast cell line BeWo. Importantly, whereas expo sure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15 Delta PGJ(2) diminishes t rophoblast differentiation. Furthermore, 15 Delta PGJ(2), but not troglitaz one, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPAR gamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPAR gamma results in opposing effe cts on trophoblast differentiation. Our results suggest that PPARy plays an important role in placental differentiation during human pregnancy.