LBH589调控Th17/Treg平衡抑制免疫性肝损伤的实验研究  

LBH589 restrains immunological liver injuries by regulating the Th17/Treg imbalance

作　　者：李晨雨[1] 张蓓[1] 潘烨[1] 杨永华[1] 李廷翠 张婧雯[1] 王建伟[1] 孙东君 张文[1] 杨丽华[1] 

机构地区：[1]青岛大学医学院免疫学教研室,266071

出　　处：《免疫学杂志》2015年第10期842-849,共8页Immunological Journal

基　　金：国家自然基金(81072398);山东省自然科学基金(2014ZRB01466);青岛大学本科生创新实验项目

摘　　要：目的建立大鼠免疫性肝损伤模型,探究Th17/Treg平衡状态与疾病进展的相关性及LBH589对Th17/Treg失衡的免疫调控。方法将雌性Wistar大鼠随机分为慢性肝损伤模型组(CC组)、干预组(LBH组)和健康对照组(HC组)3组。尾静脉注射刀豆蛋白A(Con A)建立动物模型。生化法检测肝功能,ELISA法检测肝脏纤维化指标,取肝脏做病理分析,流式细胞分析术(FCM)检测Th17细胞和Treg细胞频率变化;ELISA法检测外周血IL-17、IL-6、IL-10、TGF-β等相关细胞因子的质量浓度,免疫组化法检测肝脏局部IL-17、IL-6、IL-10、TGF-β、Foxp3、RORγt蛋白表达情况。结果与HC组比较,CC组肝功受损,纤维化指标(HA、TIMP-1)水平升高(P<0.05),肝脏结构破坏,Th17细胞频率及细胞相关因子(IL-17、IL-6等)水平升高(P<0.05),Treg细胞频率及细胞相关因子(TGF-β、IL-10、Foxp3等)水平显著升高(P<0.05),Th17/Treg比值较HC组下降(P<0.05)。LBH589干预后,与CC组相比,LBH组肝功、纤维化指标(HA、TIMP-1)水平及肝脏病理明显改善,差异有统计学意义(P<0.05);与CC组相比,LBH组Th17细胞频率及细胞其相关因子(IL-17、IL-6等)水平下降,Treg细胞频率及细胞相关因子(TGF-β、IL-10、Foxp3等)水平也下降,但Th17/Treg比值较CC组上升(P<0.05)。体外试验中,与对照组相比,各LBH治疗组IL-17、IL-6、IL-10、TGF-β等相关细胞因子的含量显著降低,差异有统计学意义(P<0.05)并呈现剂量依赖关系。结论大鼠慢性肝损伤中,存在Th17/Treg失衡,LBH589可以纠正Th17/Treg失衡状态,对肝脏进行免疫调控,抑制肝病的发展。This study designed to explore the correlation between the Th17/Treg balance and the progression of diseases, and investigate the immunological regulation of the Th17/Treg imbalance mediated by LBH589 in immunological liver injured rats. Female Wistar rats were randomly divided into three groups, including chronic control group（CC）, LBH589 group（LBH）, and health control group（HC）. The immunological liver injury models were established by caudal vein injection of con A. We found that compared with the HC group, hypohepatia,increasing liver fibrosis indexes（HA, TIMP-1, P 0.05）, and destruction of the hepatic structure were presented in the CC group; the Th17 cells and the associated cell connected factors（Foxp3, IL-17, IL-6） in CC group increased（P 0.05）, meanwhile Treg cells and the associated cell connected factors（RORγt, IL-10） increased remarkably（P 0.05）. While the ratio of Th17/Treg decreased（P 0.05） compared to the HC group. After LBH589 injection, the hepatic function, liver fibrosis and the hepatic structure in the LBH group were restored significantly compared with those in the CC group（P 0.05）. Furthermore, the LBH group also presented decreased levels of Th17 cells and the associated cell connected factors（Foxp3, IL-17, IL-6）, decreased levels of Treg cells and the associated cell connected factors（RORγt, IL-10）, but increased ratio of Th17/Treg, as compared with the CC group（P 0.05）. In vitro, compared to the control group, LBH589 decreased the levels of cell connected factors such as IL-17, IL-6, IL-10, TGF-βsignificantly（P 0.05） in a dose-dependent manner. In conclusion, the imbalance of Th17/Treg is manifested in chronic liver injury rat model, and LBH589 may correct this imbalance, thus to control the development of liver injury through immunological regulations.

关 键 词：TH17细胞 调节性T细胞 LBH589 肝损伤 

分 类 号：R575[医药卫生—消化系统]