GLUCOCORTICOID REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA ACTIVATION IN UROGENITAL SINUS MESENCHYMAL CELLS

The transforming growth factors-beta (TGF-beta-s) regulate many aspects of cell proliferation and differentiation. The TGF-beta isoforms are produced by most cell types in the biologically inactive, latent form. The physiological relevance of latent TGF-beta and the regulation of activation to the biologically active form are not well understood. Although expression of TGF-beta messenger RNA is regulated by the steroid hormone family, the mechanisms of hormonal regulation of TGF-beta activation have not been well studied. Fetal rat urogenital sinus organ cultures and derived mesenchymal cell lines (U4F, U4F1) have been established in order to analyze the expression of growth and differentiation regulatory factors which may function in mesenchymal induction of epithelial differentiation. The U4F1 cell line in chemically defined medium upon supplementation with dexamethasone (10 nM-1.4-mu-M), produced an activity which was growth inhibitory to PC-3 prostatic carcinoma epithelial cells. Analysis of phsicochemical properties and purification of activity demonstrated a 25-kDa protein was responsible for activity. The activity cross-reacted to antisera specific for TGF-beta-1,beta-2 and for TGF-beta-2 exclusively, but not with antisera to rat interferon (alpha-beta) or rat interleukin 6. Acid treatment of control (unsupplemented) conditioned medium and cultures supplemented with other steroid hormones produced identical levels of activated TGF-beta as nonacid-treated conditioned medium from dexamethasone supplemented cultures which did not increase levels of activity upon acid activation. Activity from the acid-treated control conditioned medium was neutralized by TGF-beta antibodies. These data suggest latent TGF-beta is produced constitutively by U4F1 mesenchymal cultures in steroid unsupplemented medium and these cultures are induced by dexamethasone to activate identical levels of TGF-beta. These observations may be relevant to understanding diverse aspects of glucocorticoid regulation of tissue function and suggests that TGF-beta may be relevant to paracrine and autocrine growth regulation in the developing urogenital sinus.