Original Research ARTICLE
Interleukin-1/-33 signaling pathways as therapeutic targets for endometriosis
- 1Department of Obstetrics and Gynecology,, Hyogo College of Medicine, Japan
- 2Department of Immunology, Hyogo College of Medicine, Japan
- 3The Institute of Medical Science, Department of Microbiology and Immunology, Division of Vaccine Science, The University of Tokyo, Japan
- 4Department of Surgical Pathology, Hyogo College of Medicine, Japan
- 5Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan
Endometriosis is an estrogen-dependent disease with symptoms of dysmenorrhea, chronic pain, and infertility that affects 6% to 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.
Keywords: MyD88, irak4, ST2, IL-1R1, estrogen
Received: 11 Jun 2019;
Accepted: 09 Aug 2019.
Copyright: © 2019 Kato, Yasuda, Matsushita, Ishii, Hirota, Yoshimoto and Shibahara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Koubun Yasuda, Hyogo College of Medicine, Department of Immunology, Nishinomiya, 663-8501, Hyogo, Japan, email@example.com