Estradiol and Interleukin-1β Exert a Synergistic Stimulatory Effect on the Expression of the Chemokine Regulated upon Activation, Normal T Cell Expressed, and Secreted in Endometriotic Cells

Endometriosis, commonly associated with intraperitoneal inflammation, is estrogen dependent. Possible links between the immunoinflammatory and endocrine changes observed in endometriotic women have been poorly understood. In this study, we report that estradiol (E2) and IL-1β exert a synergistic stimulatory action on RANTES (regulated upon activation, normal T cell expressed, and secreted) expression by endometriotic cells. Treatment of endometriotic cells with IL-1β had a dose-dependent effect on RANTES protein secretion and mRNA steady state levels, whereas cell treatment with E2 or progesterone had no detectable effect. Interestingly, treatment of endometriotic cells with E2 before stimulation with IL-1β resulted in a further increase in RANTES protein secretion and mRNA steady state levels, compared with IL-1β alone, whereas treatment with progesterone did not significantly affect cell responsiveness to IL-1β. Assessment of RANTES mRNA half-life revealed that cell pretreatment with E2 enhanced RANTES mRNA stability and increased gene transcription as shown by run-on analysis. Immunohistochemical analysis of RANTES in endometriotic tissue showed immunostaining to be predominant in the stroma with no noticeable differences in tissues from the proliferative and secretory phase of the menstrual cycle. This appears to be consistent with the cell culture data and indicates that RANTES expression in endometriotic tissue is not subject to cyclic variation. These findings reveal a new regulatory mechanism by which IL-1β produced by activated macrophages can in synergy with ovarian and locally produced E2 lead to enhanced macrophage and T-lymphocyte recruitment, thereby exacerbating the local immunoinflammatory process. Furthermore, the findings provide a further evidence for a close relationship between the endocrine and immunological changes observed in endometriosis.