Fractalkine/CX3CR1 is involved in the pathogenesis of endometriosis by regulating endometrial stromal cell proliferation and invasion

Abstract

Problem: Chemokines have been reported to play a sovereign role in the establishment and progression of endometriosis. Fractalkine is a chemokine that is upregulated in many inflammatory diseases including endometriosis. Fractalkine functions as a chemotactic role for lymphocytes and monocytes. In this study, we investigated the role of fractalkine/CX3CR1 in the pathogenesis of endometriosis.

Method of study: In this study, immunohistochemistry was performed on normal endometrium (taken from controls), eutopic endometrium (taken from patients with endometriosis), and ectopic tissues to analyze fractalkine/CX3CR1 expression. The levels of fractalkine in peritoneal fluid and the cell culture supernatant were examined by enzyme-linked immunosorbent assay (ELISA). Bromodeoxyuridine (BrdU) cell proliferation assay was applied to detect the proliferation of endometrial stromal cells (ESCs). The invasion of ESCs was measured by transwell invasion assay. The protein levels of Bcl2, MMP2, MMP9, p-AKT/AKT, p-p38/p38, p-JNK/JNK, and p-ERK/ERK were analyzed by Western blot.

Results: We found that the eutopic endometrium had significantly higher expression of fractalkine and CX3CR1 compared to normal endometrium, and the ectopic tissues had the highest expression. The concentrations of fractalkine in peritoneal fluid of endometriosis patients were obviously higher than that of the control and correlate very well with the severity of endometriosis. Fractalkine enhanced ESCs proliferation and invasion via activating AKT and p38 signal pathways. Moreover, high concentration of estradiol (10(-7) , 10(-6) mol L(-1) ) induced fractalkine expression while high concentration of progesterone (10(-6) , 10(-5) mol L(-1) ) inhibited fractalkine expression in ESCs.

Conclusion: The results revealed that the high levels of fractalkine in ectopic milieu promoted proliferation and invasion of ESCs through activating AKT and p38 signal pathways. Estradiol has a stimulating effect on the expression of fractalkine. The present results increase our understanding of the significance of fractalkine in the progression of endometriosis and shed some lights on the targeted fractalkine/CX3CR1 therapies.

Keywords: endometrial stromal cell; endometriosis; fractalkine/CX3CR1; invasion; proliferation.