Fluhr Herbert, Krenzer Stefanie, Stein Gerburg M, Stork Björn, Deperschmidt Margarita, Wallwiener Diethelm, Wesselborg Sebastian, Zygmunt Marek, Licht Peter
Department of Obstetrics and Gynecology, University of Greifswald, Wollweberstr. 1, 17475 Greifswald, Germany.
J Cell Sci. 2007 Dec 1;120(Pt 23):4126-33. doi: 10.1242/jcs.009761. Epub 2007 Nov 14.
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)-gamma and tumor necrosis factor (TNF)-alpha 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-gamma and TNF-alpha 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-gamma and TNF-alpha 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-gamma and TNF-alpha on ESCs could play an important role in the modulation of early implantation.
植入胚胎与母体子宫内膜之间的微妙相互作用在植入过程中起着关键作用。人子宫内膜基质细胞（ESC）表达Fas，而植入的滋养层细胞分泌Fas配体（FASLG，FasL），这表明Fas介导的信号传导在早期植入过程中可能发挥作用。在此我们表明，ESC主要对Fas介导的凋亡具有抗性，与它们的激素分化状态无关。用干扰素（IFN）-γ和肿瘤坏死因子（TNF）-α预处理ESC可使其在受到激动性抗Fas抗体刺激Fas时变得易于凋亡。将ESC与早期胚胎信号人绒毛膜促性腺激素（hCG，CGB）一起孵育不会影响它们对Fas刺激的反应。IFN-γ和TNF-α的致敏作用伴随着ESC中Fas和FLICE抑制蛋白（FLIP，CFLAR）表达的显著上调。此外，我们观察到凋亡性Fas触发时半胱天冬酶3、半胱天冬酶8和半胱天冬酶9的激活。总之，我们证明IFN-γ和TNF-α使原本抗凋亡的ESC对Fas介导的细胞死亡敏感。这可能是由于Fas表达上调，并且凋亡似乎由活性半胱天冬酶3、半胱天冬酶8和半胱天冬酶9介导。观察到的IFN-γ和TNF-α对ESC的促凋亡作用可能在早期植入的调节中起重要作用。
