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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3874-3881
Copyright © 2000 by The Endocrine Society

Original Studies

Peroxisome Proliferator-Activated Receptor-{gamma} Modulates Differentiation of Human Trophoblast in a Ligand-Specific Manner1

W. Timothy Schaiff, Matthew G. Carlson, Steven D. Smith, Roni Levy, D. Michael Nelson and Yoel Sadovsky

Departments of Obstetrics and Gynecology and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Yoel Sadovsky, M.D., Department of Obstetrics and Gynecology, Washington University School of Medicine, 4566 Scott Avenue, St. Louis, Missouri 63110. E-mail: sadovskyy{at}msnotes.wustl.edu

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) regulates the differentiation of several tissues and cell types. PPAR{gamma} was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPAR{gamma} on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPAR{gamma} expression and found that PPAR{gamma} is present in syncytiotrophoblasts 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, stimulates PPAR{gamma} activity, but has no effect on PPAR{gamma} expression. We demonstrated that the PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15{Delta}PGJ2) and the thiazolidinedione troglitazone stimulate PPAR{gamma} activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15{Delta}PGJ2 diminishes trophoblast differentiation. Furthermore, 15{Delta}PGJ2, but not troglitazone, 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 effects on trophoblast differentiation. Our results suggest that PPAR{gamma} plays an important role in placental differentiation during human pregnancy.




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