外周血HMGB1经RAGE-IL-6途径调控Th17/Treg参与子痫前期的发病  

High-mobility group box 1 protein （HMGB1） in maternal plasma affects Th17/Treg balance via receptor for advanced glycation end products（ RAGE） -IL-6 pathway in preeclamptic pregnancies

作　　者：王健 杨晶[2] 穆雅琴 朱壮彦 王喜英 张晋华[2] 蒋文渊 王晓东[2] 池玉玲 Wang Jian;Yang Jing;Mu Yaqin;Zhu Zhuangyan;Wang Xiying;Zhang Jinhua;Jiang Wenyuan;Wang Xiaodong;Chi Yuling(Institute of Immunology, School of Medicine, Shanxi Datong University, Datong 037009, Chin;the Fifth People＇s Hospital of Datong, Datong 037009, Chin;Department of Medicine, Albert Einstein College of Medicine, Bronx NY 10461, US)

机构地区：[1]山西大同大学医学院免疫学研究所,037009 [2]大同市第五人民医院,037009 [3]美国艾伯特爱因斯坦医学院,纽约,10461

出　　处：《中华微生物学和免疫学杂志》2018年第2期124-129,共6页Chinese Journal of Microbiology and Immunology

基　　金：国家自然科学基金项目（81170621）;山西省高等学校科技创新项目（2017165）;大同市科学技术发展计划项目（2016115,2017139）

摘　　要：目的 分析子痫前期患者外周血中高迁移率族蛋白B1（high mobility group box 1 pro-tein,HMGB1）与Th17、Treg细胞及细胞因子水平的关系,探讨HMGB1通过晚期糖基化终末产物受体（receptor for advanced glycation end products,RAGE）-IL-6轴影响 Th17/Treg平衡的作用机制.方法选择子痫前期患者40例（轻、重度子痫前期各20例）作为实验组,另取20例正常晚期妊娠妇女作为对照组.应用ELISA法测定外周血中HMGB1、IL-6、IL-17和TGF-β的浓度,借助RT-PCR检测外周血单个核细胞（peripheral blood mononuclear cells,PBMCs）内RAGE mRNA表达情况,通过流式细胞术检测Treg、Th17细胞比例.分选PBMC进行体外培养,经重组人HMGB1（recombinant human HMGB1,rh-HMGB1）刺激后,应用RT-PCR检测胞内RAGE、IL-6、Foxp3和RORγt mRNA的变化.结果 子痫前期外周血中HMGB1、IL-6、Th17细胞及IL-17水平明显高于正常妊娠组,且HMGB1水平与其他指标变化均呈正相关;子痫前期外周血中Treg细胞和TGF-β变化与HMGB1均呈负相关.体外rhHMGB1刺激后,PBMCs内RAGE、IL-6和RORγt mRNA表达明显增高,而Foxp3 mRNA表达降低.结论 子痫前期患者外周血中高表达的HMGB1,可能通过RAGE-IL-6信号途径,调节Th17/Treg平衡向Th17方向偏移,加重炎症反应,参与子痫前期的发病.Objective To analyze the relationships of high mobility group box 1 protein （HMGB1） with regulatory T cells （Treg）, T helper 17 cells （Th17） and cytokine secrtion in peripheral blood of gravidas with preeclampsia（PE）,and to investigate the mechanism of HMGB1 in regulating Th17/Treg ratio via receptor for advanced glycation end products （RAGE）-IL-6 pathway. Methods Forty gravi-das with mild（20 cases） and severe（20 cases） PE were recruited as experimental groups,20 heathy gravi-das in the third trimester of pregnancy were enrolled as control group. Concentrations of HMGB1,IL-6,IL-17 and TGF-β in peripheral blood of all subjects were determined by enzyme-linked immunosorbent assay （ELISA）. Real-time quantitative PCR（RT-PCR） was used to detect the expression of RAGE at mRNA lev-el in peripheral blood mononuclear cells（PBMCs）. The percentages of Treg and Th17 cells were determined by flow cytometry. RT-PCR was performed to analyze changes in the expression of RAGE,IL-6,Foxp3 and RORγt at mRNA level after the PBMCs isolated from 20 garvidas with PE were cultured in vitro and stimula-ted with recombinant human HMGB1 （rhHMGB1）. Results The levels of HMGB1,IL-6,Th17 and IL-17 in peripheral blood of gravidas with PE were significantly higher than those in the normal pregnancy group. Moreover,HMGB1 level was positively correlated with IL-6 level and ratios of Th17/Treg and IL-17/TGF-β in preeclamptic pregancies. In vitro stimulation of PBMCs with rhHMGB1 significantly enhanced the expres-sion of RAGE,IL-6 and RORγt at mRNA level, but suppressed the expression of Foxp3 at mRNA level. Conclusion Enriched HMGB1 in plasma shifts the Th17/Treg balance towards Th17 dominance via the RAGE-IL-6 pathway, which exacerbates inflammation and participates in the onset of preeclampsia during pregnancy.

关 键 词：子痫前期 高迁移率族蛋白B1 RAGE受体 Th17/Treg平衡 

分 类 号：R714.244[医药卫生—妇产科学]