Transforming growth factor-β1 attenuates expression of both the progesterone receptor and Dickkopf in differentiated human endometrial stromal cells
Transforming growth factor-β1 attenuates expression of both the progesterone receptor and Dickkopf in differentiated human endometrial stromal cells
复制标题
DOI：
10.1210/me.2007-0316
复制
发表时间：
2008-03-01
影响因子：
--
通讯作者：
Critchley, Hilary O. D.
中科院分区：
文献类型：
--
作者：
Kane, Nicole;Jones, Marius;Critchley, Hilary O. D.
TGF β 1被认为与月经相关的周期性组织重塑和炎症事件密切相关。月经是由孕激素戒断引起的;然而，其潜在机制尚不清楚。在本研究中，我们已经测试的假设，本地产生的TGF β 1可能会影响孕激素受体（PR）或Wnt拮抗剂Dickkopf-1（DKK）的表达，从而影响月经的调节。子宫内膜间质细胞（ESC）分离自子宫内膜活检样品，收集自接受妇科手术的良性适应症的患者。用TGF β 1（10 ng/ml）处理分化的ESC显著抑制编码PR和DKK的mRNA的表达。TGF β 1还减弱了培养上清液中PR的蛋白表达和DKK蛋白的分泌。内源性TGF β 1信号传导的中和消除了TGF β 1诱导的效应，显著增加了PR的表达，并增加了DKK蛋白释放水平至分化的ESC的水平，证实了TGF β 1效应的特异性。此外，在体外蜕膜化的胚胎干细胞显着增加DKK蛋白的释放。此外，虽然TGF β 1能够通过Sma和母体针对十肢麻痹（MAD）相关蛋白（SMAD）通路进行信号传导，但对DKK的抑制作用是SMAD独立的。相反，TGF β 1对PR的抑制作用依赖于SMAD信号转导。总之，这些结果表明，局部TGF β 1信号传导可以通过抑制PR的表达来增强孕酮戒断，并且可以通过抑制DKK诱导Wnt信号传导来协调与月经相关的组织重塑，我们发现DKK作为ESCs蜕膜化的结果而上调。
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.