RESUMEN
Several hundred thousand primordial follicles are present in the mammalian ovary, however, only a limited number develop to the pre-ovulatory stage, and then finally ovulate. The others, more than 99%, will be eliminated through a degenerative process called 'atresia'. The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained unknown. From many recent studies, it is suggested that the apoptosis in ovarian granulosa cells plays a crucial role in follicular atresia. Notably, death ligand-receptor interaction and subsequent intracellular signalling have been demonstrated to be the key mechanisms regulating granulosa cell apoptosis. In this review, we provide an overview of granulosa cell apoptosis regulated by death ligand-receptor signalling. The roles of death ligands and receptors [Fas ligand (FasL)-Fas, tumour necrosis factor (TNF)alpha-TNF receptor (TNFR), and TNFalpha-related apoptosis-inducing ligand (TRAIL)-TRAIL receptor (TRAILR)] and intracellular death-signal mediators [Fas-associated death domain protein (FADD), TNF receptor 1-associated death domain protein (TRADD), caspases, apoptotic protease-activating factor 1 (Apaf1), TNFR-associated factor 2 (TRAF2), and cellular FLICE-like inhibitory protein (cFLIP), etc.] in granulosa cells will be discussed.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/fisiología , Atresia Folicular/fisiología , Células de la Granulosa/fisiología , Porcinos , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Proteína Ligando Fas/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Femenino , Células de la Granulosa/citología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Folículo Ovárico , Receptores de Muerte Celular/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Human CD8+ cytotoxic T lymphocyte (CTL)-mediated cytotoxicity in xenograft recipients is an important obstacle for successful xenotransplantation of pig organs into humans. In our previous study, we demonstrated that xenocytotoxicity of human CD8+ CTL detrimental to pig endothelial cells (PEC) is mediated mainly by the Fas/FasL apoptotic pathway. Furthermore, we developed new methods to prevent this CTL killing by extracellular remodeling using overexpression of human decoy Fas antigen and membrane-bound human FasL on pig xenograft cells. The cellular FLICE-inhibitory protein (c-FLIP), a caspase-8 inhibitor that lacks the cysteine domain, is a negative regulator of death receptor-mediated apoptosis. c-FLIP proteins exist as long (c-FLIP(L)) and short (c-FLIPs) splice variants, both capable of protecting cells from death receptor-mediated apoptosis. In this report, we have demonstrated that both pig c-FLIPs and pig c-FLIP(L) significantly inhibit human CD8+ CTL-mediated xenocytotoxicity toward stably transfected PEC, although the expression level of pig Fas antigen on cell surface was not changed. These data suggested that intracellular remodeling with overexpression of pig c-FLIP in xenograft cells may decrease the innate cellular responses against xenografts, facilitating long-term xenograft survival.