title: IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis.
abstract: Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10+Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β. Compared with peripheral CD4+T cells, endometrial CD4+T cells highly expressed IL-27 receptors, especially the ectopic endometrium. Under external (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and local (estrogen, IL-6 and TGF-β) environmental regulation, IL-27 from macrophages and endometrial stromal cells (ESCs) induces IL-10 production in Th17 cells in vitro and in vivo. This process may be mediated through the interaction between c-musculoaponeurotic fibrosarconna (c-Maf) and retinoic acid-related orphan receptor gamma t (RORγt), and associated with the upregulation of downstream B lymphocyte-induced maturation protein-1 (Blimp-1). IL-10+Th17 cells, in turn, stimulate the proliferation and implantation of ectopic lesions and accelerate the progression of endometriosis. These results suggest that IL-27 is a pivotal regulator in endometriotic immune tolerance by triggering Th17 cells to produce IL-10 and promoting the rapid growth and implantation of ectopic lesions. This finding provides a scientific basis for potential therapeutic strategies aimed at preventing the development of endometriosis, especially for patients with high levels of IL-10+Th17 cells.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.|Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Kai-Kai
authors.initials: KK
authors.lastname: Chang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People's Republic of China.|Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, People's Republic of China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jin
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Mei
authors.affiliation: Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wei
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.|Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People's Republic of China.
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Shao
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.|Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032, People's Republic of China.
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, People's Republic of China.|Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032, People's Republic of China.|Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, People's Republic of China.
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Li
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D018450:Disease Progression; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: C508609:IL10 protein, human; D015850:Interleukin-6; D007378:Interleukins; C495607:MAF protein, human; C464565:MYDGF protein, human; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051257:Proto-Oncogene Proteins c-maf; C539900:RORC protein, human; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1