The cell to cell interaction between peritoneal macrophages and endometrial stromal cells via Stat3 activation in human endometriosis

Abstract

Objectives: Endometriosis frequently develops in the female pelvic cavity. This suggests that the peritoneal environment that contains various free-fl oating cells such as macrophages and endometrial cells derived from refl uxed menstrual blood may contribute to the development of endometriosis. We previously reported that the proportion of active macrophages was elevated in ascites from patients with endometriosis, and in another study, activated macrophages reportedly released several cytokines into the peritoneal cavity. This study focused on the interactions between macrophages and endometrial stromal cells (ESCs) in the development of endometriosis. Methods: The phenotype of macrophages in the ascites from patients with endometriosis was determined by immunocytochemistry. Soluble factors in ascites and conditioned medium from human macrophages and ESCs in co-culture system were quantified by the Cytokine Array Kit. Next, we investigated the significance of macrophages for proliferation and Stat3 activation of ESCs by using co-cultured cells. Furthermore, pSTAT3 expression of peritoneal foci of endometriosis was assessed by immunohistochemistry. Finally, the effects of corosolic acid (CA), a triterpenoid compound, on proliferation and Stat3 activation of ESCs in co-cultures were evaluated. Results: The total number of CD163+ macrophages (M2 macrophages) in ascites from the endometriosis group was signifi cantly higher than that of the control group. The cytokine array study detected that the production of GM-CSF, RANTES, IL-1 receptor antagonist, and MCP-1 were up-regulated in ascites from patients with endometriosis and in conditioned medium from co-cultured cells (c-CM). Coculture with M2 macrophages signifi cantly up-regulated ESC proliferation and Stat3 activation in ESCs in vitro. Immunohistochemically, Stat3 was activated in both epithelial and stromal cells in endometriotic lesions. When the inhibitory eff ect of a Stat3 inhibitor, CA on ESC was investigated, CA inhibited ESC proliferation and Stat3 activation induced by c-CM. Conclusions: These fi ndings indicated that the interactions between M2 macrophages and ESCs via Stat3 activation may play indispensable roles in the development of endometriosis. Targeting Stat3 signals may aid the treatment of patients with endometriosis.