IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype

In endometriosis, M2 macrophages (M phi) are dominant and promote the development of endometriosis lesions. However, the factor(s) which induces M2 M phi are unknown. In the present study, we focused on interleukin (IL)-33, known as an alarmin and investigated its expression and its role in endometriosis, especially from the point of the relevance with M phi. The expression of IL-33 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors was obtained and used to measure IL-33 concentration. Endometriotic stromal cells (ESC) and M phi derived from patients were used for in vitro experiments. IL-33 was detected in the epithelium and stromal cells of endometriotic lesions. The mean IL-33 concentration in the cystic fluid of endometriomas was significantly higher than that in non-endometriomas (2.2 ng/ml vs. 0.02 ng/ml, P < 0.01). IL-1 beta induced IL-33 mRNA expression in ESC via p38 MAPK activation. With IL-33 stimulation, peritoneal M phi polarized to M2 M phi and produced IL-1 beta mRNA with a 2.2-fold increase, which was negated with soluble ST2, a decoy receptor of IL-33. IL-33, derived from endometriotic lesions, stimulated M phi to produce IL-1 beta, which results in increasing IL-33 production in ESC. This cycle may continue to exacerbate the endometriotic lesions.