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

Abstract

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 (E(2)) and IL-1beta 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-1beta had a dose-dependent effect on RANTES protein secretion and mRNA steady state levels, whereas cell treatment with E(2) or progesterone had no detectable effect. Interestingly, treatment of endometriotic cells with E(2) before stimulation with IL-1beta resulted in a further increase in RANTES protein secretion and mRNA steady state levels, compared with IL-1beta alone, whereas treatment with progesterone did not significantly affect cell responsiveness to IL-1beta. Assessment of RANTES mRNA half-life revealed that cell pretreatment with E(2) 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-1beta produced by activated macrophages can in synergy with ovarian and locally produced E(2) 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.

Increased expression of interleukin-1 receptor type 1 in active endometriotic lesions

“…The inhibitory activity of IL-1ra was even shown to be enhanced by soluble IL-1RII and hindered by soluble IL-1RI (Burger et al 1995). According to our and other previous data, endometriotic cells are highly sensitive and responsive to IL-1 (Akoum et al 1995(Akoum et al , 2000(Akoum et al , 2002, and secrete increased levels of angiogenic factors compared with endometrial cells from normal women (Lebovic et al 2000). Also, IL-1RI is, in contrast to the decoy inhibitory IL-1RII, slightly released in the culture medium of endometrial and endometriotic cells (personal data).…”

“…IL-1 would have more pronounced effects on adhesion in endometriosis (Sillem et al 1999). Activation and recruitment of immune cells into endometriotic implants can be mediated by other secreted cytokines and chemokines such as MCP-1, RANTES, IL-6, and IL-8, which were found to be up-regulated by IL-1 in endometriotic cells (Akoum et al 1995(Akoum et al , 1996(Akoum et al , 2002) and could in turn promote IL-1 secretion by activated immune cells. IL-1 induces secretion of IL-8 and IL-6, which exhibit proangiogenic properties (Akoum et al 1996.…”

“…Increased concentrations of the cytokine were found in the peritoneal fluid of women with endometriosis (Fakih et al 1987, Mori et al 1992, Taketani et al 1992 as well as in ectopic endometrial implants (Bergqvist et al 2001). In our previous studies, endometriotic cells showed a marked secretion of monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), IL-6 and IL-8 following exposure to IL-1, and displayed a remarkable sensitivity for IL-1 (Akoum et al 1995(Akoum et al , 1996(Akoum et al , 2002. In keeping with our findings, data from Lebovic et al (2000) suggest that the ability of IL-1b to activate an angiogenic phenotype in endometriotic stromal cells, but not in stromal cells from normal endometrium, is mediated by the functional signaling receptor IL-1RI.…”

Deficiency of Immunophilin FKBP52 Promotes Endometriosis

“…MCP-1 and RANTES are well-known chemokines whose concentrations are high in peritoneal fluid of women with endometriosis 61,62 and whose secretions are promoted by estrogen. 34,35 In human endometriotic stromal cells, inflammatory stimuli induce secretion of these chemokines, and estrogen enhances their secretion. 34,35 In vitro studies in human endometrial stromal cells have shown that adding P 4 does not suppress estrogen-induced expression of these chemokines, 34,35 suggesting P 4 resistance in endometriotic cells.…”

“…34,35 In human endometriotic stromal cells, inflammatory stimuli induce secretion of these chemokines, and estrogen enhances their secretion. 34,35 In vitro studies in human endometrial stromal cells have shown that adding P 4 does not suppress estrogen-induced expression of these chemokines, 34,35 suggesting P 4 resistance in endometriotic cells. Our present findings that Fkbp52 null mice with endometriotic lesions have enhanced levels of chemokines in their peritoneal fluids corroborates well with reduced PR and FKBP52 expression and unchanged ER␣ expression in ectopic lesions.…”