Endometriosis: Secretion of interleukin-6 by human endometriotic cells and regulation by proinflammatory cytokines and sex steroids

Abstract

Endometriosis is generally associated with an immunoinflammatory process that takes place in the peritoneal cavity of patients. Interleukin (IL)-6, a multifunctional cytokine involved in numerous immunological and proliferative processes, has been found at high concentrations in the peritoneal fluid of endometriosis patients. The purpose of this study was to investigate the ability of endometriotic cells to produce IL-y and to assess the regulation of its secretion by proinflammatory cytokines and sex steroids. Cultures of human endometriotic cells were exposed to different concentrations of cytokines and sex steroid hormones for varying periods of time. IL-6 secretion was measured using an enzyme-linked immunosorbent assay. Endometriotic cells spontaneously released IL-6 in culture. IL-1 beta and tumour necrosis factor (TNF)-alpha (0.1-100.0 ng/ ml) potentiated IL-y secretion in a time- and dose-dependent manner. Interferon-gamma (0.4-400 ng/ml) induced a dose-related increase in IL-6 secretion and showed a synergistic effect on that secretion in combination with TNF-alpha (10 ng/ ml). Either spontaneous or cytokine-induced IL-6 secretion was inhibited by progesterone (10(-8)-10(-5) M) and danazol (10(-6) M), whereas oestradiol (10(-8)-10(-5) M) had a limited inhibitory effect. The antiprogestin RU486 (10(-8)-10(-4) M) antagonized the inhibitory effects of progesterone and danazol, but showed agonist action when used alone. These findings indicate that endometriotic tissue may actively contribute to the biological changes observed in the peritoneal fluid of endometriosis patients. They also provide new insights into the mechanisms of action of progesterone and those of danazol and RU486 used in the treatment of endometriosis.

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

“…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.…”

“…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. Data from Lebovic et al (2000) showed an enhanced production of angiogenic molecules such as vascular endothelial growth factor (VEGF) and IL-6 in response to IL-1b in endometriotic cells, as compared with endometrial cells from normal endometrium, and increased expression of IL-1RI mRNA, suggesting a role for IL-1b ligand binding and signaling via IL-1RI.…”

“…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.…”

Relationship between cytokines and the embryotoxicity of hydrosalpingeal fluid

“…The cytokine, which appears to mediate numerous physiologic and pathogenic processes, acts on a wide variety of cells and regulated immune responses, acute-phase responses of the liver, hematopoiesis, neuronal functions, and osteoclastogenesis (21). The cytokine may also have important functions in reproductive physiology, including the regulation of ovarian steroid production, folliculogenesis, and early events related to implantation (22,23). The fact that I L-6 is positively correlated with BDR may explain in part, why some hydrosalpingeal fluid samples are not embryotoxic.…”

Endometriosis and Angiogenic Factors

“…IL-6 may also have important functions in reproductive physiology, including the regulation of ovarian steroid production, folliculogenesis and early events related to implantation. (Jacobs et al,1992); (Akoum et al, 1996). Both eutopic and ectopic endometrium are known to produce IL-6 .…”