Interleukin 1 Receptor Type Ii In Endometriosis The Role Of Research In The Mechanisms And Biological Treatment

Endometriosis is a common gynecological disorder,affecting at least 10%of reproductive-aged women,and is characterized by the growth of endometrial tissue outside of the uterine cavity.Retrograde menstruation is one of the proposed mechanisms for the presence of endometrial cells in ectopic sites.However,it cannot explain why the displaced cells survive in women with endometriosis and not in healthy women.An immunological or inflammatory aetiology has been conjectured,as suggested by the increased concentrations of activated macrophages, cytokines,T cells and B cells in patients with endometriosis.Cytokines are key mediators of intercellular communication within the immune system,and exert proliferative,cytostatic,chemoattractant or differentiative effects on a variety of target cells.The cytokine IL-1 plays a central role in the regulation of inflammation and immune responses. Elevated concentration of IL-1 has been reported by several authors in the peritoneal fluid of patients with endometriosis.Increased levels of IL-1βmRNA expression have also been identified in the peritoneal macrophages of patients with mild endometriosis.Our previous studies have demonstrated that human endometrium expresses IL-1 receptor typeⅡ(IL-1RII)and IL-1RII protein levels are markedly reduced in women with endometriosis.IL-1RII mRNA expression is significantly decreased in endometriosis,particularly during the early stages of the disease(stagesⅠandⅡ),and this may contribute to the etiology of the disease.The present study examined the effect of IL-1RII on eutopic endometrial stromal cells(ESCs)of endometriosis.We measured IL-1β-stimulated IL-6 and IL-8 levels in ESCs following treatment with soluble IL-1RII.In addition,recombinant IL-1RII adenovirus(rAd-RII) over-expressing IL-1RII was constructed and introduced into ESCs.Our study revealed that IL-1βsignificantly increased the production of IL-6 and IL-8,and that this effect was counteracted by sIL-1RII. IL-1β-induced production of IL-8 was significantly decreased in ESCs by rAd-RII.Furthermore,differences in protein expression between the rAd-RII and PBS groups were evaluated by two-dimensional electrophoresis.We next evaluated the in vitro results in a nude mouse model of endometriosis.We constructed the nude mouse model of endometriosis and investigated whether sIL-1RII can decrease the effect of IL-1 in the endometriotic-like lesions in vivo.The results showed that administration of recombinant sIL-1RII could inhibit the growth of implant,decrease the expression of Bcl-2 and VEGF in the lesions and the levels of VEGF and IL-8 in peripheral blood and peritoneal fluids in the nude mouse model of endometriosis. In conclusion our results show that IL-1RII may counteract the actions of IL-1βin both endometriotic stromal cells and the nude mouse model.The results provide further insights into the mechanism of immunologic modulation of IL-1RII during the process of endometriosis, and suggest that IL-1RII may be developed as a new drug for the treatment of endometriosis.However,these findings also indicate that the pathogenesis of endometriosis is multifactorial and involves many cellular mediators.Thus,an effective therapeutic agent for endometriosis would be a combination of compounds that not only prevents the development of endometriosis lesions but also would be effective against the growth of established lesions and abolish the abnormal microenvironment of the lesion.