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Expression and Regulation of Glucocorticoid Receptor in Human Placental Villous Fibroblasts

Departments of Obstetrics and Gynecology (M.-J.L., S.S.K.), Microbiology (Z.W., M.J.G.), Pathology (H.Y.), Urology (N.S., S.K.L.), and Pharmacology (S.K.L.), New York University School of Medicine, New York, New York 10016; Department of Obstetrics and Gynecology (Y.M., L.Y., S.G.), Yale University School of Medicine, New Haven, Connecticut 06520-8063; and Department of Pathology (R.N.B.), Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Seth Guller, Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, 339 FMB, P.O. Box 208063, New Haven, Connecticut 06520-8063. E-mail: seth.guller{at}yale.edu.

The human placenta is a glucocorticoid (GC)-responsive organ consisting of multiple cell types including smooth muscle cells, fibroblasts, and trophoblast that demonstrate changes in gene expression after hormone treatment. However, little is known about the relative expression or activity of the GC receptor (GR) among the various placental cell types. Normal term human placentas were examined by immunohistochemistry using either GR phosphorylation site-specific antibodies that are markers for various activation states of the GR or a GR antibody that recognizes the receptor independent of its phosphorylation state (total GR). We found strong total GR and phospho-GR immunoreactivity in stromal fibroblasts of terminal villi, as well as perivascular fibroblasts and vascular smooth muscle cells of the stem villi. Lower levels of both total GR and phospho-GR were found within cytotrophoblast cells relative to fibroblasts, whereas syncytiotrophoblast showed very little total GR or phospho-GR immunoreactivity. This pattern holds true for immunoblot analysis of extracts from cell fractions cultured ex vivo. In cultured placental fibroblasts, phosphorylation of GR increased upon short-term GC treatment, consistent with a role for GR phosphorylation in receptor transactivation. Total GR levels were reduced by nearly 90% after long-term hormone treatment; however, this down-regulation was independent of changes in GR mRNA levels. These findings demonstrate that GR levels in fibroblasts can be modulated by changes in hormone exposure. Such cell type-specific differences in GR protein expression and phosphorylation may provide the means of differentially regulating the GC response among the cells of the human placenta.

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