Abnormal interleukin 1 receptor types I and II gene expression in eutopic and ectopic endometrial tissues of women with endometriosis.

Interleukin-1 (IL1) is believed to play a central role in the immuno-inflammatory process associated with endometriosis. IL1 triggers cell activation via its receptor type I (IL1R1), but its receptor type II (IL1R2) is known instead as a scavenger that buffers the cytokine's effects. Our previous studies have shown increased expression of IL1R1 in active endometriotic implants compared to normal and endometriosis women-derived endometrial tissues, and a simultaneous decrease in IL1R2 expression at the protein level. In the present study, in situ hybridization demonstrated a noticeable decrease in IL1R2 mRNA hybridization score in eutopic and matched ectopic endometrial tissues of women with endometriosis compared to normal women in the stroma (P<0.001 and P<0.001, respectively) and the epithelium (P<0.01 and P<0.05, respectively), whereas IL1R1 mRNA hybridization score was higher only in the ectopic implants, with a statistically significant difference in the stroma (P<0.05). This was corroborated by RT-PCR analysis of IL1R1 and IL1R2 mRNAs in ectopic (P<0.05 and P<0.05, respectively) and matched eutopic (P=0.22 and P<0.05, respectively) endometrial tissues from women with endometriosis compared to endometrial tissues from normal women. The decrease in IL1R2 mRNA levels in eutopic endometrial tissue of endometriosis women, and the concomitant increase in IL1R1 mRNA levels in ectopic implants, reveal a profound defect in IL1R 1 and IL1R2 gene expression which may accentuate the capability of this tissue to respond to IL1 and favor its ectopic growth.

Estradiol and interleukin-1beta 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 (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.

Insights into endometriosis-associated endometrial dysfunctions: a review.

Endometriosis is defined as the presence of ectopic endometrial-like tissue outside the uterus cavity. This disease, afflicting women during their reproductive age, is mainly associated with pelvic pain and infertility. Sampson's theory which supports the ability of endometrial fragments from retrograde menstruations to slough through fallopian tubes and reach peritoneal environment has been recognized as the most plausible explanation for endometriosis during many years. However, further studies provided evidence that fundamental abnormal changes may occur within the eutopic endometrium of women with endometriosis compared to that of women without endometriosis. These dysfunctions included genetic predisposition, genes aberrantly expressed such as matrix metalloproteinases, Hox genes, integrins, anti-apoptotic genes Bcl-2, but also steroid hormones, immuno-inflammatory factors and angiogenesis. This review aims at summarizing and emphasizing a non exhaustive panel of biochemical and molecular factors abnormally expressed in the eutopic endometrium and related to the pathogenesis of endometriosis.

Imbalance in the peritoneal levels of interleukin 1 and its decoy inhibitory receptor type II in endometriosis women with infertility and pelvic pain.

OBJECTIVE: To evaluate the levels of interleukin-1beta (IL1beta) and its inhibitory soluble interleukin-1 receptor type II (IL1R2) in the peritoneal fluid (PF) of normal women and patients with endometriosis suffering from pelvic pain and infertility. DESIGN: Retrospective study using ELISA to measure peritoneal fluid IL1beta and soluble IL1R2. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Sixty-eight normal women and 154 women with endometriosis. INTERVENTION(S): Peritoneal fluid samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): IL1beta and soluble IL1R2 concentrations in the PF samples. RESULT(S): This study showed a marked decrease in peritoneal soluble IL1R2 levels in women with endometriosis compared to normal women and a concomitant increase in the levels of IL1beta. Both fertile and infertile women with endometriosis had lower soluble IL1R2 and higher IL1beta concentrations than fertile women having a normal gynecological status, but the difference was more significant in infertile endometriosis patients. Compared with normal controls, the decrease in soluble IL1R2 levels was less significant in women with endometriosis than without pelvic pain, whereas the increase in IL1beta concentrations was statistically significant only in women with endometriosis reporting pelvic pain. CONCLUSION(S): This study revealed an imbalance between IL1beta and its decoy inhibitory receptor type 2 in women with endometriosis, which was particularly obvious in those who were infertile, and suggests that a defect in the local control of IL1 may be involved in the pathophysiology of endometriosis and related infertility.

Elevated levels of macrophage migration inhibitory factor in the peripheral blood of women with endometriosis.

OBJECTIVE: To evaluate the concentrations of macrophage migration inhibitory factor (MIF) in the peripheral blood of normal women and patients with endometriosis. DESIGN: Retrospective study using ELISA to measure peripheral blood MIF. SETTING: Gynecology clinic and human reproduction research laboratory. PATIENT(S): Thirty-eight normal women and 55 women with endometriosis. INTERVENTION(S): Peripheral blood samples were obtained a few days before laparoscopy. MAIN OUTCOME MEASURE(S): The MIF concentrations in blood serum. RESULT(S): This current study showed a 364% increase in MIF concentrations in women with endometriosis as compared to normal women. A significant increase was seen in endometriosis stages I-II, but a more marked increase was observed in the more advanced stages of the disease (III-IV). Both fertile and infertile women with endometriosis had higher levels of MIF than normal controls, but the difference was more significant in infertile women with endometriosis. Women with endometriosis with no pelvic pain had higher levels of MIF than normal controls, but a more significant increase in MIF levels was observed in women with endometriosis reporting pelvic pain. CONCLUSION(S): This study showed a marked increase in MIF concentrations in the peripheral blood of women with endometriosis and a relationship with disease progress, and suggests that MIF may be involved in endometriosis-related pain and infertility.