Regulation of Fas Ligand Expression by Estradiol and Progesterone in Human Endometrium1

Abstract

Implantation involves a complex set of events, including apoptosis in endometrial cells. Apoptosis in human endometrium coincides with the implantation window, suggesting a potential role for steroid hormones in its regulation. Fas ligand (FasL) is one of the mediators of apoptosis in differentiated cells and in embryonic development. Interaction of FasL with its receptor, Fas, induces apoptosis through autocrine and paracrine signaling. We hypothesized that FasL expression in human endometrium is cycle-dependent and that sex steroid hormones regulate FasL expression. We first studied menstrual cycle-dependent expression of FasL in human endometrium by immunohistochemistry in 24 samples. We then investigated the in vitro regulation of FasL expression by ovarian steroid hormones. Throughout the menstrual cycle immunohistochemical staining intensity was stronger in the functional layer of endometrium than it was in the basal layer. FasL immunoreactivity increased gradually through the mid- and late-proliferative phases in both endometrial stromal and glandular cells. Strong FasL expression was observed throughout the late-proliferative and secretory phases. Semiquantitative reverse transcription-polymerase chain reaction analysis in cultured endometrial glandular cells demonstrated that estradiol and progesterone stimulate FasL mRNA expression. Western blot analysis in endometrial glandular and stromal cells in culture revealed that estradiol alone and in combination with progesterone up-regulated FasL protein expression. These results suggest that estradiol and progesterone may have a role in the regulation of maternal immunotolerance for the implantation of a semiallograft embryo by inducing FasL expression. We speculate that increased FasL expression may mediate the apoptosis of endometrial cells and thus may play a role in trophoblast invasion.

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

“…Many factors, for example IL8, vascular endothelial growth factor (VEGF), chemokine ligand 2 (CCL2), various components of the extracellular matrix, the early embryonal signal hCG as well as the hormones progesterone and estradiol, have been shown to regulate FasL in human ESCs (Harada et al, 2004;Kayisli et al, 2003;Selam et al, 2001). So far, the expression of FasL by ESCs has been interpreted as a mechanism to regulate the population of immune cells present at the implantation site, thereby mediating immune tolerance in respect to the trophoblast.…”

Two Concepts on the Immunological Aspect of Blastocyst Implantation

“…RCAS1 has been recognized to play a role in immune evasion of the tumor cells. Selam et al [83] showed up-regulation of FasL in human endometrium by estradiol and progesterone. Kasyisli et al [30] demonstrated that hCG stimulates FasL mRNA and protein in endometrial cells, and observed that cells of early pregnancy deciduas express strong FasL immunoreactivity.…”

Melatonina: modulador de morte celular

“…Its ligand (Fas-L/ CD178) is a 37 kDa protein belonging to the superfamily of the TNFs [20][21][22][23] . Fas and Fas-L are engaged in the cell death process; after the interaction of Fas-L on the cell surface with the Fas receptor, there is formation of aggregates in the form of trimers, which bond to adaptor protein FADD (Fas associated death domain) present in the cytoplasm.…”