title: mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile.
abstract: It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Shurong
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Surgery, Cancer hospital, Fudan University, Shanghai, PR China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Zhengting
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yaofei
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, PR China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Sichang
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Maochen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Gastroenterology, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D009025:Morpholines; D016264:Dextran Sulfate; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases