TGF-WS Induce Smad-Dependent Signaling And Apoptosis In Human Endometrial And Endometriotic Cells

Abstract

The transforming growth factor-13 (TGF-13) superfamily play a prominent role in various cellular processes. TGF-I3s are highly expressed in the peritoneal fluid of patients with endometriosis, as well as in endometriotic sites. Thus, TGF-I3s might he involved in biological processes leading to endometriosis. This study aimed to analyse the effects of TGF-131 or TGF-132 on cell numbers, on apoptosis and signal transduction in endometrial and endometriotic cells in vitro.

Immortalized human endometrial stromal (T-HESC), epithelial (HES), endometriotic stromal (22B) and epithelial (12ZVK) cell lines were used. Cells were treated with or without TGF-131 or TGF- 2, respectively, and the cell numbers were counted. By using specific inhibitors targeting TGF- signaling, Smad and apoptotic pathways were studied.

Our results showed that: (1) TGF-131 or TGF-132 significantly decreased cell numbers of all cell lines at high initial cell numbers. The decrease in cell numbers of endometrial cells was higher (T-HESC=61%, HES=29%) compared to endometriotic cells (22B=24%, 12ZVK=21%). (2) A TI3RI inhibitor completely blocked the TGF-13-induced reduction in cell numbers. A Smad3 inhibitor partly blocked it, suggesting that the Smad pathway is the main pathway of TGF-13 signaling in endometrial and endometriotic cells. Additionally, TGF-131 or TGF-132 reduced the cell numbers of both endometrial and endometriotic cells through apoptosis via the mitochondrial pathway. This effect was Smad-dependent. In addition, TI3Rl inhibitor completely blocked TGF-13 induced PAI-l secretion.

In conclusion, TGF-f31 or TGF-132 reduced cell numbers by stimulating apoptosis and PAI-l production, because we recently found that bioactive PAI-l reduced cell adhesion to the extracellular matrix. Since the TGF-I3s dramatically increased secretion of PAI-l, thus may play an important role in the pathogenesis of endometriosis. The Smad pathway is the main pathway of TGF-13 signaling in endometrial and endometriotic cells. TGF-I3s induces apoptosis via the mitochondrial pathway in endometrial and endometriotic cells.