title: 3, 3'-Diindolylmethane alleviates steatosis and the progression of NASH partly through shifting the imbalance of Treg/Th17 cells to Treg dominance.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: She
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Fuping
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Tongji Hospital Tongji University, Shanghai China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Jiyao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: jiang.wei@zs-hospital.sh.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D002478:Cells, Cultured; D002794:Choline / Q000008:administration & dosage; D004032:Diet / Q000009:adverse effects; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000166:cytology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology; D058504:Th17 Cells / Q000187:drug effects* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D008715:Methionine; D002794:Choline; C016392:3,3'-diindolylmethane
keywords: 3, 3′-diindolylmethane; Aryl hydrocarbon receptor; Nonalcoholic steatohepatitis; Regulatory T cells; Th17 cells; Toll like receptor 4