The kinase p38 Regulates Peroxisome Proliferator Activated Receptor-γ in Human Trophoblasts

Deficiency of either the mitogen-activated protein kinase p38 or the nuclear receptor PPARγ results in disrupted vasculogenesis and abnormal development of the murine placenta. In addition, PPARγ regulates differentiation of human trophoblasts. Here we tested the hypothesis that p38 plays an important role in the regulation of PPARγ in primary human trophoblasts. We initially confirmed that cultured trophoblasts derived from normal term human placentas express p38 as well as its functional phosphorylated form. Whereas PPARγ did not alter p38 expression, p38 inhibitors diminished the transcriptional activity of PPARγ in primary trophoblasts. In addition, inhibition of p38 resulted in marked attenuation of PPARγ-stimulated hCG production by cultured trophoblast. Our data support an effect of p38 on PPARγ protein stability because p38 inhibition led to reduced expression of PPARγ protein without a significant effect on PPARγ mRNA, and this reduction was blocked by the protease inhibitor MG-132. Together, these data indicate that p38 regulates PPARγ expression and activity in term human trophoblasts. Cross talk between p38 and PPARγ signaling may play a role in modulating differentiation and function of the human placenta.