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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.

SUBMITTER: Kato T 

PROVIDER: S-EPMC6714064 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Kato Toru T   Yasuda Koubun K   Matsushita Kazufumi K   Ishii Ken J KJ   Hirota Seiichi S   Yoshimoto Tomohiro T   Shibahara Hiroaki H  

Frontiers in immunology 20190822


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  ...[more]

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