Transforming growth factor-β1 attenuates expression of both the progesterone receptor and Dickkopf in differentiated human endometrial stromal cells

TGF beta 1 is thought to be intimately involved in cyclic tissue remodeling and inflammatory events associated with menstruation. Menstruation is initiated by progesterone withdrawal; however, the underlying mechanisms are not well understood. In the present study, we have tested the hypothesis that locally produced TGF beta 1 may influence expression of progesterone receptor (PR) or the Wnt antagonist Dickkopf-1 (DKK) with consequential impact on regulation of menstruation. Endometrial stromal cells (ESC) were isolated from endometrial biopsy samples collected from patients undergoing gynecological procedures for benign indications. Treatment of differentiated ESC with TGF beta 1 (10 ng/ml) significantly inhibited the expression of mRNAs encoding PR and DKK. TGF beta 1 also attenuated the protein expression of PR and secretion of DKK proteins in culture supernatants. Neutralization of endogenous TGF beta 1 signaling abolished the TGF beta 1-induced effects, significantly increased expression of PR, and increased DKK protein release levels to that of differentiated ESCs, confirming the specificity of the TGF beta 1 effect. Additionally, in vitro decidualization of ESCs significantly augmented DKK protein release. Moreover, although TGF beta 1 was capable of signaling via the Sma- and mothers against decapentaplegic (MAD)-related protein (SMAD) pathway, the inhibitory effect on DKK was SMAD independent. Conversely, the inhibitory effect of TGF beta 1 on PR was dependent on SMAD signal transduction. In conclusion, these results suggest that local TGF beta 1 signaling can potentiate progesterone withdrawal by suppressing expression of PR and may coordinate tissue remodeling associated with menstruation by inducing Wnt-signaling via inhibition of DKK, which we found to be up-regulated as a consequence of decidualization of ESCs.