title: Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Greifswald, Wollweberstr. 1, 17475 Greifswald, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Fluhr
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krenzer
authors.forename: Gerburg M
authors.initials: GM
authors.lastname: Stein
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
authors.forename: Margarita
authors.initials: M
authors.lastname: Deperschmidt
authors.forename: Diethelm
authors.initials: D
authors.lastname: Wallwiener
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.forename: Marek
authors.initials: M
authors.lastname: Zygmunt
authors.forename: Peter
authors.initials: P
authors.lastname: Licht
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D018929:Cell Culture Techniques; D016923:Cell Death / Q000502:physiology; D002469:Cell Separation; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003656:Decidua / Q000166:cytology / Q000378:metabolism; D004347:Drug Interactions; D004717:Endometrium / Q000166:cytology*; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology*; D019169:Jurkat Cells; D016685:Mitomycin / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000502:physiology*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D006063:Chorionic Gonadotropin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011374:Progesterone; D004958:Estradiol; D016685:Mitomycin; D007371:Interferon-gamma; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9