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Steroid Regulation of Human Placental Integrins: Suppression of ₂ Integrin Expression in Cytotrophoblasts by Glucocorticoids¹

Departments of Obstetrics and Gynecology (J.S.R., Y.M., S.G.) and Biochemistry (S.G.), New York University School of Medicine, New York, New York 10016; and the Department of Orthopedics, Mount Sinai Medical Center (R.J.M.), New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Seth Guller, Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, Tisch Hospital Room 531, New York, New York 10016.

Maintenance of uterine-placental attachment during human pregnancy may depend at least partly on adhesive interactions between cytotrophoblasts and their extracellular matrix (ECM). Such interactions are often mediated by integrins, signal-transducing heterodimeric transmembrane glycoproteins. We previously showed that glucocorticoid (GC) suppressed the expression of collagen and laminin in human placenta; here we show that GC also modulates the expression by human cytotrophoblasts of the integrin subunits ₂ and ß₁, components of a known receptor for these ECM ligands. Cytotrophoblasts were isolated from human term placentas, cultured up to 4 days in the presence of 0–1000 nM dexamethasone (DEX), and assayed for 1) integrin messenger RNA (mRNA) levels by Northern hybridization, 2) integrin subunit synthesis after [³⁵S]methionine labeling, or 3) cell surface integrin levels after ¹²⁵I labeling by lactoperoxidase. In four independent experiments, 100 nM DEX reduced mRNA levels for integrin ₂ to 6 ± 1% of the control value. This effect was similar between 1–4 days of treatment and was dose dependent between 1–1000 nM DEX. Cortisol treatment (100 nM) inhibited levels of integrin ₂ mRNA, but 100 nM testosterone, estradiol, and progesterone were less effective, suggesting that this response was specific to GC. In immunoprecipitation studies, treatment of cytotrophoblasts with 100 nM DEX for 2 days reduced the rates of synthesis of the ₂ integrin subunit as well as its expression on the cell surface to 1–10% of control levels. DEX effects on the ß₁ integrin subunit were less dramatic. DEX reduced ß₁ mRNA levels to only 69 ± 8% of control levels, a smaller reduction compared with effects on ₂ integrin mRNA. DEX inhibited ß₁ protein synthesis and cell surface expression to 60–70% of control levels. In all experiments, DEX had no effect on total protein synthesis. Thus, our results demonstrate that GC treatment specifically and markedly down-regulates expression of ₂ integrin subunit by human cytotrophoblasts. This finding is consistent with the concept that uterine-placental adherence across gestation may be regulated by coordinate effects on ECM ligands and cellular adhesion receptors.

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