title: Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis.
abstract: Inflammatory bowel disease is characterized by dysregulated immune responses in inflamed intestine, with dominance of interleukin-17 (IL-17)--producing cells and deficiency of regulatory T (Treg) cells. The aim of this study was to investigate the effect and mechanisms of sirolimus, an inhibitor of the mammalian target of rapamycin, on immune responses in a murine model of Crohn's disease. Murine colitis was induced by intrarectal administration of 2,4,6-trinitrobenzene sulphonic acid at day 0. Mice were then treated intraperitoneally with sirolimus daily for 3 days. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. Sirolimus treatment significantly decreased all macroscopic, microscopic and histopathological parameters of colitis that were analysed. The therapeutic effects of sirolimus were associated with a down-regulation of pro-inflammatory cytokines tumour necrosis factor-α, IL-6 and IL-17A. Intriguingly, sirolimus administration resulted in a prominent up-regulation of the regulatory cytokine transforming growth factor-β. Supporting the hypothesis that sirolimus directly affects the functional activity of CD4+ CD25+ Treg cells, we observed a remarkable enhancement of FoxP3 expression in colon tissues and isolated CD4+ T cells of sirolimus-treated mice. Simultaneously, sirolimus treatment led to a significant reduction in the number of CD4+ IL-17A+ T cells in the mesenteric lymph node cells as well as IL-17A production in mesenteric lymph node cells. Therefore, sirolimus may offer a promising new therapeutic strategy for the treatment of inflammatory bowel disease.
authors.affiliation: Department of Microbiology and Immunology, Guangdong Pharmaceutical University, Guangzhou, China. huiyin0103@yahoo.com.cn
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.forename: Xiangyong
authors.initials: X
authors.lastname: Li
authors.forename: Bobin
authors.initials: B
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Baohong
authors.initials: B
authors.lastname: Yuan
authors.forename: Qian
authors.initials: Q
authors.lastname: Ni
authors.forename: Shilian
authors.initials: S
authors.lastname: Hu
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Gu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C098680:Il17a protein, mouse; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D020381:Interleukin-17; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D020123:Sirolimus
keywords: T helper type 17 cells; colitis; inflammation; regulatory T cells; sirolimus