Progesterone-dependent release of transforming growth factor-beta1 from epithelial cells enhances the endometrial decidualization by turning on the Smad signalling in stromal cells

Endometrial decidualization results from the differentiationof stromal cells in an ovarian steroid-sensitive manner. Humanendometrial tissues obtained from fertile women at various stagesof the menstrual cycle were subjected to immunohistochemistryto localize the components of the transforming growth factor-beta(TGF-ß) system. TGF-ß receptor-I and -IIexpression was higher in stromal cells than in epithelial cellsduring the secretory phase while no such variation was observedduring the proliferative phase. The expression of phosphorylatedSmad3 (pSmad2/3), an activated form of a component of the TGF-ßsignalling pathway, and translocation of pSmad2/3 from the cytoplasmto the nucleus were more pronounced in secretory endometrium.In coculture of human endometrial epithelial with stromal cells,each isolated from the proliferative endometrium, administrationof progesterone stimulated decidualization as well as TGF-ßsignalling activation in stromal cells. Progesterone also significantlyelevated the concentration of TGF-ß1 in the coculturemedium. Careful manipulation of the coculture, i.e. selectiveaddition and omission of the cellular components, showed thatthis progesterone-induced increase in secretion of TGF-ß1come mainly from epithelial cells. Moreover, administrationof TGF-ß1 (10 ng/ml) directly to cultured stromalcells enhanced the expression of prolactin as well as pSamd2/3even without progesterone. Taken together, our present datasupport the notion that progesterone induces stromal decidualizationindirectly, i.e. by enhancing the expression and secretion ofTGF-ß1 from epithelial cells. The secreted, epithelial-derivedTGF-ß1 then acts on adjacent stromal cells, at leastin part, to turn on Smad signalling that could lead to stromaldecidualization.