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

Abstract

Endometrial decidualization results from the differentiation of stromal cells in an ovarian steroid-sensitive manner. Human endometrial tissues obtained from fertile women at various stages of the menstrual cycle were subjected to immunohistochemistry to localize the components of the transforming growth factor-beta (TGF-beta) system. TGF-beta receptor-I and -II expression was higher in stromal cells than in epithelial cells during the secretory phase while no such variation was observed during the proliferative phase. The expression of phosphorylated Smad3 (pSmad2/3), an activated form of a component of the TGF-beta signalling pathway, and translocation of pSmad2/3 from the cytoplasm to the nucleus were more pronounced in secretory endometrium. In coculture of human endometrial epithelial with stromal cells, each isolated from the proliferative endometrium, administration of progesterone stimulated decidualization as well as TGF-beta signalling activation in stromal cells. Progesterone also significantly elevated the concentration of TGF-beta1 in the coculture medium. Careful manipulation of the coculture, i.e. selective addition and omission of the cellular components, showed that this progesterone-induced increase in secretion of TGF-beta1 come mainly from epithelial cells. Moreover, administration of TGF-beta1 (10 ng/ml) directly to cultured stromal cells enhanced the expression of prolactin as well as pSamd2/3 even without progesterone. Taken together, our present data support the notion that progesterone induces stromal decidualization indirectly, i.e. by enhancing the expression and secretion of TGF-beta1 from epithelial cells. The secreted, epithelial-derived TGF-beta1 then acts on adjacent stromal cells, at least in part, to turn on Smad signalling that could lead to stromal decidualization.

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…TGF-b production is regulated by ovarian sex hormones and enables several aspects of immunosuppression in the FRT at different stages of the menstrual cycle Takahashi et al 1994;Wira and Rossoll 2003;Kim et al 2005;Maurya et al 2013). Accordingly, hormone-regulated fluctuations occur in systemic and uterine Treg-cell populations, with an estrogen-regulated increase at the time of ovulation (Arruvito et al 2007).…”

Endometrium from women with endometriosis shows increased proliferation activity

“…All of the endometrial tissue specimens were at the mid or late proliferative phase of the menstrual cycle. The protocol for endometrial cell isolation and preparation for immunohistochemistry was as described previously (9,10). The immunohistochemically stained slides were evaluated with a computer program (Image Pro Plus 4.5; Media Cybernetics, Bethesda, MD), which determined the degree of staining per unit area or number of cells.…”

Genistein reduces angiogenesis and apoptosis in women with endometrial hyperplasia

“…3,5 In addition, a significant correlation between steroid-receptor expression and TGFβ expression has also been demonstrated. 5 TGFβ acts as a cell-growth inhibitor, 7 and ERα inhibits TGFβ signaling via a nongenomic mechanism. 7 In a recent study, 8 we tested the therapeutic action of the isoflavone genistein on endometrial hyperplasia.…”

“…2 Chronic exaggerated estrogenic stimulation may induce synthesis of its estrogen receptors (ERs) and also of progesterone receptors, 3 which are thus present at high levels in the hyperplastic endometrium. 4 Moreover, estradiol (E 2 ) induces the synthesis of different mitogenic factors, including VEGF and its receptor 5,6 and EGF, which are promoters of endometrial proliferation. 3,5 In addition, a significant correlation between steroid-receptor expression and TGFβ expression has also been demonstrated.…”

“…4 Moreover, estradiol (E 2 ) induces the synthesis of different mitogenic factors, including VEGF and its receptor 5,6 and EGF, which are promoters of endometrial proliferation. 3,5 In addition, a significant correlation between steroid-receptor expression and TGFβ expression has also been demonstrated. 5 TGFβ acts as a cell-growth inhibitor, 7 and ERα inhibits TGFβ signaling via a nongenomic mechanism.…”