The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β
The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β
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子宫内膜基质细胞和巨噬细胞之间的串扰通过分泌 IL-10 和 TGF-β 损害子宫内膜异位症中 NK 细胞的细胞毒性。
DOI：
10.1530/rep-17-0342
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发表时间：
2017
期刊：
影响因子：
3.8
通讯作者：
Ming-Qing Li
中科院分区：
文献类型：
--
作者：
Hui-Li Yang;Wen-Jie Zhou;Kai-Kai Chang;Jie Mei;Li-Qing Huang;Ming-Yan Wang;Yi Meng;Si-Yao Ha;Da-Jin Li;Ming-Qing Li
子宫内膜异位症（EMS）患者NK细胞功能障碍导致月经期子宫内膜碎片回流至腹腔的免疫逃逸。子宫内膜间质细胞（ESCs）和淋巴细胞之间的相互通讯促进了EMS的发生。然而，这些通信的机制对自然杀伤（NK）细胞的细胞毒性在肿瘤周围环境中仍然是很大程度上未知。为了模拟局部免疫微环境，构建了EMS患者的ESCs与单核细胞来源的巨噬细胞或ESCs、巨噬细胞和NK细胞的共培养系统。通过ELISA评估共培养单元中的细胞因子水平。流式细胞仪检测NK细胞功能分子的表达。采用细胞计数试剂盒-8和细胞毒活性测定法分析NK细胞的体外行为。与ESCs和巨噬细胞共同孵育后，NK细胞的CD 16、NKG 2D、穿孔素和IFN-γ的表达以及活性和细胞毒活性均显著下调。ESCs与巨噬细胞共培养体系中IL-1 β、IL-10和TGF-β的分泌增加。在体外，抗IL-10受体β中和抗体（αhIL-10 R β）或αTGF-β可部分逆转ESCs和巨噬细胞对NK细胞的上述作用。提示巨噬细胞与ESCs的相互作用可能通过刺激IL-10和TGF-β的分泌，下调NK细胞的杀伤活性，进而引发异位碎片的免疫逃逸，促进EMS的发生和发展。
The dysfunction of NK cells in women with endometriosis (EMS) contributes to the immune escape of menstrual endometrial fragments refluxed into the peritoneal cavity. The reciprocal communications between endometrial stromal cells (ESCs) and lymphocytes facilitate the development of EMS. However, the mechanism of these communications on cytotoxicity of natural killer (NK) cells in endometriotic milieus is still largely unknown. To imitate the local immune microenvironment, the co-culture systems of ESCs from patients with EMS and monocyte-derived macrophages or of ESCs, macrophages and NK cells were constructed. The cytokine levels in the co-culture unit were evaluated by ELISA. The expression of functional molecules in NK cells was detected by flow cytometry (FCM). The NK cell behaviors in vitro were analyzed by cell counting kit-8 and cytotoxic activation assays. After incubation with ESCs and macrophages, the expression of CD16, NKG2D, perforin and IFN-γ, viability and cytotoxicity of NK cells were significantly downregulated. The secretion of interleukin (IL)-1β, IL-10 and transforming growth factor (TGF)-β in the co-culture system of ESCs and macrophages was increased. Exposure with anti-IL-10 receptor β neutralizing antibody (αhIL-10Rβ) or αTGF-β could partly reverse these effects of ESCs and macrophages on NK cells in vitro. These results suggest that the interaction between macrophages and ESCs downregulates cytotoxicity of NK cells possibly by stimulating the secretion of IL-10 and TGF-β, and may further trigger the immune escape of ectopic fragments and promote the occurrence and the development of EMS.