IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis.
IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis.
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IL-27 通过 c-Maf/ROR gamma t/Blimp-1 信号触发 Th17 细胞产生 IL-10，促进子宫内膜异位症的进展
DOI：
10.1038/cddis.2017.95
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发表时间：
2017-03-16
影响因子：
9
通讯作者：
Li MQ
中科院分区：
文献类型：
--
作者：
Chang KK;Liu LB;Jin LP;Zhang B;Mei J;Li H;Wei CY;Zhou WJ;Zhu XY;Shao J;Li DJ;Li MQ
子宫内膜异位症是一种雌激素依赖性炎症性疾病。抗炎细胞因子IL-10在子宫内膜异位症中也增加。Th 17细胞产生IL-10对于限制自身免疫和炎症反应至关重要。然而，诱导产生IL-10的Th 17细胞的机制在很大程度上仍然未知。本研究探讨IL-10分泌型Th 17细胞在子宫内膜异位症中的分化机制及作用。在此，我们报道了子宫内膜异位症患者腹腔液中IL-10+ Th 17细胞显著增加，同时沿着IL-27、IL-6和TGF-β的升高。与外周血CD 4 + T细胞相比，子宫内膜CD 4 + T细胞高表达IL-27受体，尤其是异位内膜。在体外和体内实验中，巨噬细胞和子宫内膜间质细胞（ESCs）的IL-27在体外（2，3，7，8-四氯二苯并对二恶英，TCDD）和局部（雌激素、IL-6和TGF-β）环境调节下诱导Th 17细胞产生IL-10。这一过程可能是通过c-肌腱膜纤维肉瘤蛋白（c-Maf）与维甲酸相关孤儿受体γ t（RORγt）之间的相互作用介导的，并与下游B淋巴细胞诱导成熟蛋白-1（Blimp-1）的上调有关。IL-10+ Th 17细胞反过来刺激异位病灶的增殖和植入，并加速子宫内膜异位症的进展。这些结果表明，IL-27通过触发Th 17细胞产生IL-10并促进异位病灶的快速生长和植入，在异位免疫耐受中起关键调节作用。这一发现为旨在预防子宫内膜异位症发展的潜在治疗策略提供了科学依据，特别是对于具有高水平IL-10+ Th 17细胞的患者。
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.