Regulation of Fas Ligand Expression by IL-8 in Human Endometrium

Abstract

Numerous cytokines and growth factors are synthesized in the endometrium. IL-8 is one of these cytokines regulating endometrial function. It is a neutrophil chemoattractant/ activating factor and a potent angiogenic agent. IL-8 is elevated in the peritoneal fluid of women with endometriosis. We have previously demonstrated a direct proliferative effect of IL-8 on endometrial stromal cells. We hypothesized that increased levels of IL-8 in the endometriotic environment could up- regulate Fas ligand (FasL) expression in endometrial cells and may be relevant for the development of a relative local immunotolerance in endometriosis by inducing apoptosis of cytotoxic T lymphocytes. To test our hypothesis, we studied the in vitro regulation of FasL expression and apoptosis by IL-8 in endometrial cells. Western blot analysis in endometrial stromal, glandular, and Ishikawa cells revealed that IL-8 up- regulated FasL protein expression in these cells. By semiquantitative RT-PCR analysis, IL-8 does not alter the expression of either Fas or FasL mRNA levels in these cells. Immunocytochemistry results from endometrial stromal cells treated with IL-8 demonstrated an up-regulation of FasL protein expression. IL-8 decreased apoptosis rate in endometrial stromal cells as evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay. We observed an increased apoptotic rate in Jurkat (T lymphocyte line) cells plated on endometrial stromal cells previously treated with IL-8. We speculate that increased FasL expression by IL-8 may induce apoptosis of T lymphocytes and thus produce a local immunotolerant environment for the development of ectopic implants.

Diethylstilbestrol Induces Rat Spermatogenic Cell Apoptosis in Vivo through Increased Expression of Spermatogenic Cell Fas/FasL System

“…More importantly, the observation that the number of apoptotic cells is highest in seminiferous tubule stages where both Fas and FasL expression was high reinforced the idea that these two proteins expressed in spermatogenic cells are the main modulators of death. Interestingly, in the female, strong FasL expression occurs in the endometrium in estrogen-dependent late proliferative and secretory phases (49). Additionally, in female rats, expression of FasL protein and mRNA levels in ovarian cell increases upon estrogen treatment (50).…”

Endocrine‐Immune Interactions in Human Endometrium

“…However, chemokines are also involved in cellular proliferation, differentiation, and apoptosis. 61,62 In addition, chemokines play a role in angiogenesis, hematopoiesis, tumorigenesis and antitumoral effects, and inflammation. 63,64 Chemokines are 8-10-kDa polypeptides.…”

Molecular aspects of development and regulation of endometriosis

“…However, this regulation is lost in endometriosis [77]. Conversely, expression of the pro-apoptotic protein Fas is unchanged while its ligand, FasL, is upregulated in endometriotic tissue as well as the peritoneal fluid of women with endometriosis [93,94]. There is evidence to suggest that macrophage derived growth factors, including platelet-derived growth factor and transforming growth factor beta (TGF-β), may stimulate Fas mediated apoptosis of immune cells, which may contribute to an immune-privileged environment for endometriotic cell survival [94].…”

“…Conversely, expression of the pro-apoptotic protein Fas is unchanged while its ligand, FasL, is upregulated in endometriotic tissue as well as the peritoneal fluid of women with endometriosis [93,94]. There is evidence to suggest that macrophage derived growth factors, including platelet-derived growth factor and transforming growth factor beta (TGF-β), may stimulate Fas mediated apoptosis of immune cells, which may contribute to an immune-privileged environment for endometriotic cell survival [94]. Furthermore, upregulated expression of survivin, decreased terminal effector caspases and DNA fragmentation factor 45 in endometriotic tissues may be a reflection of resistance against apoptosis at ectopic sites [77].…”