Altered expression of interleukin-18 in the ectopic and eutopic endometrium of women with endometriosis
Introduction
Endometriosis is a common benign gynecologic disease that affects about 10% of women of reproductive age (Oku et al., 2004). The exact pathogenesis of this enigmatic disease is still unclear. To date, the theory of retrograde menstruation that postulates reflux of shed endometrial tissue through the fallopian tube with implantation on the peritoneal surface is widely accepted. Although dissemination of endometrial cells into ectopic locations during menses appears to be a common phenomenon, ectopic implantation of these cells only occurs infrequently. It seems that menstrual debris in women with endometriosis may be more prone to implant and invade the peritoneum or ovary than in normal women. An inappropriate immunologic response in the local peritoneal environment may play a crucial role in survival and development of the implanted ectopic endometrium. Increased release of inflammatory cytokines is an important component of the immunologic response. It has been shown that the expression levels of some cytokines in the eutopic endometrium of women with endometriosis differ from that of normal women (Arici, 2002, Jolicoeur et al., 1998, Khan et al., 2003).
Interleukin (IL)-18 plays an important role in immunomodulatory and anti-tumor process. IL-18 is produced as a 24 kDa precursor that requires cleavage by IL-1-converting enzyme (also called caspase-1) in order to generate its biologically active 18 kDa monomer (Ghayur et al., 1997, Gu et al., 1997). IL-18, together with IL-12, induces interferon (IFN)-γ and initiates production of pro-inflammatory cytokines. IL-18 also promotes T-helper 1 (Th1) responses and cytotoxic activity of natural killer (NK) cells (Takeda et al., 1998). Moreover, IL-18 stimulates macrophages to induce cyclooxygenase (COX)-II and, subsequently, prostaglandins (PGs), which mediate various biological responses such as pain (Kashiwamura et al., 2002). A previous study indicated that IL-18 was constitutively expressed in endometrial epithelial cells and stromal cells throughout the menstrual cycle (Yoshino et al., 2001).
A study from our hospital has suggested that IL-18 concentrations in peritoneal fluid (PF) were significantly lower in patients with endometriosis than in women without endometriosis (Zhang et al., 2004). We hypothesized that IL-18 might be involved in the pathogenesis of endometriosis and that expression levels of IL-18 might be different in the eutopic endometrium of patients with endometriosis and normal women. In the present study, we have tried to determine the expression of IL-18 in the eutopic and ectopic endometrium of patients with endometriosis. We determined also the expression of IL-18 in endometrium at the different phases of the menstrual cycle of women with or without endometriosis.
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Patient population
Fifty-seven women voluntarily participated in this study. Written consent from all women and approval by the Institutional Review Committee of the Medical School, Zhejiang University, was obtained for this study. None of the participants had pelvic inflammatory disease or cancer, and none had received any hormonal therapies 3 months prior to the present study.
The diagnosis of endometriosis was confirmed by visual impression at the time of surgery and histological examination of resected
Immunohistochemical analysis
Immunohistochemical staining with anti-IL-18 antibody was detected in both the glandular epithelial and stromal cells of eutopic endometrium and endometriotic lesions. Fig. 1 shows that IL-18 expression was localized in the cytoplasm of glandular epithelial and stromal cells. There was no signal detected in the negative controls.
Semi-quantitative RT-PCR analysis
RT-PCR analysis indicated that IL-18 mRNA was expressed in all samples. As shown in Table 2, the relative level of IL-18 mRNA expression in ectopic endometrium (0.73 ±
Discussion
The expression of IL-18 in the ectopic and eutopic endometrium of women with endometriosis has been investigated. We found that IL-18 mRNA levels were significantly lower in the ectopic and eutopic endometrium in women with endometriosis than in normal women. We demonstrated also that expression levels of IL-18 mRNA were significantly higher at the secretory phase than the proliferative phase in normal women, but not in women with endometriosis.
It is well-known that IL-18 plays an important
Acknowledgement
This work was supported in part by National Science Foundation of China (No. 30471642).
References (29)
- et al.
A brief review of recent data on some cytokine expressions at the materno-foetal interface which might challenge the classical Th1/Th2 dichotomy
J. Reprod. Immunol.
(2002) Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine
Fertil. Steril.
(1994)- et al.
Immunoexpression of hepatocyte growth factor and c-Met receptor in the eutopic endometrium predicts the activity of ectopic endometrium
Fertil. Steril.
(2003) - et al.
A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization
Fertil. Steril.
(2004) - et al.
Role of the endometrial tripod interleukin-18, -15 and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization–embryo transfer failure
Fertil. Steril.
(2005) - et al.
Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium
Fertil. Steril.
(1991) - et al.
Abnormal retinal vascular development in IL-18 knockout mice
Lab. Invest.
(2004) - et al.
Defective NK cell activity and Th1 response in IL-18-deficient mice
Immunity
(1998) - et al.
Decreased natural killer cell activity in endometriosis patients: relationship to disease pathogenesis
Fertil. Steril.
(1994) - et al.
Decreased levels of interleukin-18 in peritoneal fluid but not in serum of patients with endometriosis
Fertil. Steril.
(2004)
Local cytokines in endometrial tissue: the role of interleukin-8 in the pathogenesis of endometriosis
Ann. N. Y. Acad. Sci.
Interleukin-18 acts as an angiogenesis and tumor suppressor
FASEB J.
Immuno-endocrine interactions in early pregnancy
Hum. Reprod.
Cytokines in implantation
Hum. Reprod. Update
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2022, Fertility and SterilityCitation Excerpt :IL-18, which is consistently among the 4 most strongly weighted factors (Figs 1B, 2B, and 3B), is produced by many cell types, including stromal and epithelial cells in the endometrium, where it regulates activation and cytokine production of uNK cells and is implicated in vascular remodeling in pregnancy (69–72). Consistent with our findings of a negative association with endometriosis, transcriptional analyses of endometrial biopsy specimens showed that IL-18 mRNA expression was higher in normal women than in women with endometriosis (72). Also consistent with our findings of great variability among a patient population with infertility (Supplemental Table 2) are reports that in patients with recurrent implantation failure, IL-18 is lower in the preimplantation endometrium in some patients and higher in others, underscoring the need for patient stratification in immune-targeted therapies in this population (73, 74).
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The authors have equal contribution to the present study.