Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis

Abstract

Endometriosis is an estrogen-dependent disease with symptoms of dysmenorrhea, chronic pain, and infertility that affects 6–10% of women of reproductive age. Medical or surgical therapy, such as administration of an anti-gonadotropin or ovarian cystectomy, provide effective pain relief. However, neither therapy can be used for patients wishing to become pregnant. Despite the high morbidity, the pathogenesis of endometriosis has not been well-elucidated. Several inflammatory cytokines are reported to participate in the onset of endometriosis. Here, we examined the role of interleukin (IL)-1/IL-33 signaling in the development of endometriosis using a mouse model of endometriosis. Endometriotic lesion volume was significantly reduced in Il33 −/− and Il1r1 −/− mice, and almost completely suppressed in Myd88 −/− mice. Mice intraperitoneally administered with an antibody against IL-1 receptor 1 (IL-1R1) or IL-33 developed limited endometriotic lesions. Oral administration of an inhibitor against IL-1R-associated kinase 4 (IRAK4), a downstream signal molecule of MyD88, also suppressed lesion formation. Furthermore, even after the development of cystic lesions the IRAK4 inhibitor prevented the enlargement of lesions. These treatments all significantly reduced cellular proliferation, shown by decreased Ki-67 expression. These results reveal that IL-1/IL-1R1, IL-33/IL-33R and associated downstream signaling molecules are involved in the pathogenesis of endometriosis, and may provide novel therapeutic targets for endometriosis.

Pelvic endometriosis and natural killer cell immunity

“…It was suggested that cytokine production of NK cells in the peritoneal fluid in women suffering with endometriosis might be changed by dienogest or OCP because of the change of NCRs (Figure 2B). 80 Recently, we have reported the role of IL‐1/IL‐33 signaling in the onset and development of endometriosis 13 . In the absence of IL‐33 or IL‐1R1, endometriotic lesions were reduced.…”

“…There are many reports suggesting that women with endometriosis have lower success rates of IVF‐ET 11,12 . More importantly, many researchers have reported changes in the functions of immune cells in the peritoneal fluid and cytokine production such as IL‐1, 13,14 IL‐6, 14,15 IL‐8, 14 IL‐33, 13 TNF‐α, 15‐18 IFN‐γ, 16,17 and VEGF 19,20 by immune cells as the cause of infertility. Changes in endometrial lymphocytes and endometrial receptivity have also been reported 21‐23 .…”

Endometriosis: Etiology, pathobiology, and therapeutic prospects

“…Endometriosis lesions are often found attached to the peritoneal wall or in association with the ovaries where they are exposed to PF containing immune cells, cytokines, and growth factors (Bain and Jenkins, 2018;Zondervan et al, 2020). Pro-inflammatory factors increased in the PF of women with endometriosis include interleukins (IL-1, IL-6, IL-8, and IL-33), tumor necrosis factor (TNF), and insulin-like growth factor 1 (Cheong et al, 2002;Forster et al, 2019;Kato et al, 2019). Many cells may contribute to this complex mix of factors with different lines of evidence implicating immune cells, mesothelial cells, as well as endometrial tissue arriving in the peritoneum via retrograde menstruation.…”

“…Members of the IL-1 cytokine family (including IL-33 and IL-1b) and their receptors appear to be promising targets for new therapies with evidence from mouse models that monoclonal antibodies directed against these ligands, as well as inhibitors of their MyD88 downstream signaling pathway, can reduce lesion volume (Kato et al, 2019). IL-33 is released by damaged cells and has been implicated in activation of allergic inflammation-related eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (IL-C2s) through its receptor ST2 (Chan et al, 2019).…”

New Therapeutics in Endometriosis: A Review of Hormonal, Non-Hormonal, and Non-Coding RNA Treatments

“…Inflammatory cytokines are involved in the pathogenesis of endometriosis. The role of interleukin (IL)-1/IL-33 signaling in the development of endometriosis and the effect of the Il-1R-associated kinase (IRAK4, a downstream signal of MyD88) inhibitor have been studied in a mouse model [ 113 ]. IL-1 is involved in the development of endometriosis and MyD88 signaling is essential to the growth of endometriotic lesions.…”