Regulation of FAS Ligand Expression by Chemokine Ligand 2 in Human Endometrial Cells

Abstract

Human endometrium is a dynamic tissue under the influence of numerous hormones, growth factors, and cytokines interacting to maintain a balance of cellular growth, differentiation, and apoptosis. We have previously demonstrated that several factors including interleukin-8, extracellular matrix, and steroid hormones modulate FASLG, one of the apoptotic molecules, in human endometrium. Chemokine ligand 2 (CCL2), a monocyte chemoattractant and activating factor, is a cytokine involved in endometrial function. CCL2 is elevated in the peritoneal fluid of women with endometriosis. We hypothesize that increased levels of CCL2 in the endometriotic environment may upregulate FASLG expression in human endometrial stromal cells and induce a local immunotolerance in endometriosis. To test our hypothesis, we studied the in vitro regulation of FASLG expression and apoptosis by CCL2 in endometrial stromal cells. Western blot analysis revealed that CCL2 upregulated FASLG protein expression in cultured endometrial stromal cells. Based on semiquantitative RT-PCR analysis, CCL2 did not alter either FAS or FASLG mRNA expression in endometrial stromal cells. Immunocytochemistry results from the same cells treated with CCL2 demonstrated upregulation of FASLG protein expression. CCL2 did not change rate of apoptosis in endometrial stromal cells as evaluated by TUNEL assay. However, an increased apoptotic rate was detected in Jurkat (T lymphocytes) cells cocultured with endometrial stromal cells previously treated with CCL2. We speculate that increased FASLG expression by CCL2 may induce apoptosis of T lymphocytes and thus produce an immunotolerant environment for the development of ectopic implants.

Change of proinflammatory cytokines follows certain patterns after induction of endometriosis in a mouse model

“…Monocyte chemoattractant protein 1 is a chemotactic cytokine that can influence both innate immunity, through its effects on monocytes, and adaptive immunity, via T helper cell polarization (18). An earlier study (19) demonstrated that MCP-1 could substantially increase the production of Fas ligand in cultured endometrial and stromal cells, and, interestingly, this increased production did not up-regulate the apoptosis of endometrial cells but increased the apoptosis of T lymphocytes. This might result in the development of immunotolerance by increasing the apoptosis of leukocytes and thereby helping the survival of ectopic endometrial cells (19).…”

Immune-inflammation gene signatures in endometriosis patients

“…The significant elevation of FAS in ectopic tissues contradicts a recent study that showed, by means of immunohistochemistry, decreased FAS expression in the epithelial cells of ectopic tissues (37). As such, we attribute increased FAS expression to the resident immune cells, which are likely subjected to apoptosis by increased FasL in the peritoneal fluid of endometriosis patients (38). Overall, our data characterize endometriosis as a disease where many biologic and immune-related pathways are dysregulated.…”

Modulation of the maternal immune system by the pre-implantation embryo

“…For example, CCL11, which was upregulated in both intercaruncular and caruncular tissue in pregnant animals attracts CCR3-expressing TH2 cells [31], and CCL2, which was only upregulated in caruncular tissue, attracts leukocytes expressing its receptor CCR2 [31,32]. Consistent with this is the association of CCL2 upregulation with immune tolerance in endometriosis, a mechanism suggested to act through its action on the FAS ligand, inducing apoptosis of T lymphocytes [33]. The FAS ligand, along with FAS and the downstream effector molecules FADD and caspase were all upregulated in pregnant animals in both tissue types.…”