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First published online 14 November 2007
doi: 10.1242/jcs.009761

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Interferon- and tumor necrosis factor- sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

Herbert Fluhr^1,2,*, Stefanie Krenzer^2,*, Gerburg M. Stein³, Björn Stork³, Margarita Deperschmidt², Diethelm Wallwiener², Sebastian Wesselborg³, Marek Zygmunt^1, and Peter Licht^2,4

¹ Department of Obstetrics and Gynecology, University of Greifswald, Wollweberstr. 1, 17475 Greifswald, Germany
² Department of Obstetrics and Gynecology, University of Tübingen, Calwerstr. 7, 72076 Tübingen, Germany
³ Department of Internal Medicine I, University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
⁴ Fertility Center Nuremberg, Agnesgasse 2, 90403 Nuremberg, Germany

Author for correspondence (e-mail: zygmunt{at}uni-greifswald.de)

Accepted 11 September 2007

The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas-mediated signaling during early implantation. Here we show that ESCs are primarily resistant to Fas-mediated apoptosis independently of their state of hormonal differentiation. Pre-treatment of ESCs with interferon (IFN)- and tumor necrosis factor (TNF)- sensitizes them to become apoptotic upon stimulation of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN- and TNF- was accompanied by a significant upregulation of Fas and FLICE-inhibitory protein (FLIP, CFLAR) expression in ESCs. Additionally, we observed an activation of caspase 3, caspase 8 and caspase 9 upon apoptotic Fas triggering. In summary, we demonstrate that IFN- and TNF- sensitize primarily apoptosis-resistant ESCs to Fas-mediated cell death. This might be due to an upregulation of Fas expression, and apoptosis seems to be mediated by active caspase 3, caspase 8 and caspase 9. The observed pro-apoptotic effect of IFN- and TNF- on ESCs could play an important role in the modulation of early implantation.

Key words: Endometrium, Implantation, Apoptosis, Fas

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