3, 3′-diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance
3, 3′-diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance
复制标题
DOI：
10.1016/j.intimp.2014.09.024
复制
发表时间：
2014-12-01
影响因子：
5.6
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Liu, Yun;She, Weimin;Jiang, Wei
本研究旨在探讨3,3'-二吲哚甲烷（DIM）对蛋氨酸-胆碱缺乏（MCD）饮食诱导的小鼠非酒精性脂肪性肝炎（NASH）的影响及其潜在机制。将NASH小鼠分为不同组，分别给予或不给予不同浓度的DIM，持续8周。分析了DIM在NASH进展过程中对调节性T细胞（Treg）/辅助性T细胞17（Th17）失衡的体内外影响。在体内通过阻断CD25或白细胞介素-17（IL-17），分别消除Treg或Th17亚群的相应功能。此外，借助芳香烃受体（AhR）拮抗剂CH223191和抗Toll样受体4（TLR4）中和抗体，设计体外DIM孵育实验，以探讨AhR（细胞色素P450 1A1（CYP1A1）、细胞色素P450 1B1（CYP1B1））和TLR4在DIM纠正Treg/Th17失衡时所起的作用。值得注意的是，在NASH小鼠模型中，DIM减轻了肝脏脂肪变性和炎症，使Treg/Th17失衡从MCD饮食诱导的Th17占优势转变为Treg占优势。在体外，DIM不仅显著上调纯化的脾脏CD4(+) T细胞中叉头框蛋白P3（Foxp3，Treg特异性）的信使核糖核酸（mRNA），还增强了这些Treg细胞的免疫抑制功能。此外，DIM显著上调MCD饮食小鼠CD4(+) T细胞中CYP1A1和CYP1B1的蛋白表达，而下调TLR4的蛋白表达。而且，阻断AhR会减弱DIM调节Treg/Th17失衡的作用，而阻断TLR4则会增强其作用。综上所述，DIM可作为一种潜在的治疗NASH的候选药物，因其能显著诱导Treg占优势从而减轻肝脏内炎症，这为我们提供了一条线索，即富含DIM的十字花科蔬菜可能是NASH相关肝病患者的一种保护因素。（C）2014爱思唯尔公司版权所有。
This study was designed to discuss the effects of 3, 3'-diindolylmethane (DIM) on methionine-choline-deficient (MCD)-diet induced mouse nonalcoholic steatohepatitis (NASH) and the potential mechanisms. NASH mice were administrated with or without DIM at different concentrations for 8 weeks. Both the in-vivo and in-vitro effects of DIM on Treg/Th17 imbalance during NASH progression were analyzed. The in-vivo blocking of CD25 or IL-17 was performed to respectively deplete respective function of Treg or Th17 subset. Besides, with the assistance of AhR antagonist CH223191 and anti-TLR4 neutralizing antibody, we designed the in-vitro DIM-incubation experiments to discuss the roles of aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1B1) and toll-like receptor 4 (TLR4) on DIM's effects when shifting Treg/Th17 imbalance. Notably, in NASH mouse models, DIM alleviated hepatic steatosis and inflammation, and shifted the Treg/Th17 imbalance from MCD diet-induced Th17 dominance to Treg dominance. In-vitro, DIM not only significantly up-regulated the mRNAs of Foxp3 (Treg-specific) in purified spleen CD4(+) T cells, but also enhanced the immunosuppressive function of these Treg cells. Besides, DIM significantly up-regulated the proteins of CYP1A1 and CYP1B1 whereas down-regulated those of TLR4 on CD4(+) T cells from MCD-diet mice. Moreover, blocking AhR attenuated while blocking TLR4 enhanced the effects of DIM when regulating Treg/Th17 imbalance. Conclusively, DIM could be used as a potential therapeutic candidate to treat NASH based on its dramatic induction of Treg dominance to alleviate intra-hepatic inflammation, suggesting us a clue that the dietary cruciferous vegetables (containing abundant DIM) might exist as a protective factor for patients with NASH-related liver diseases. (C) 2014 Elsevier B.V. All rights reserved.