title: SEW2871 protects from experimental colitis through reduced epithelial cell apoptosis and improved barrier function in interleukin-10 gene-deficient mice.
abstract: Loss of intestinal epithelial barrier function including typical tight junction changes and epithelial cell apoptosis plays an important role in Crohn's disease. SEW2871, a selective sphingosine-1-phosphate type-1 receptor agonist, has been proven to be efficient in protecting against colitis in IL-10(-/-) mice in our previous study. Here we performed additional studies to investigate whether treatment with SEW2871 was associated with an improved epithelial barrier function in IL-10(-/-) mice. SEW2871 was administered by gavage at a dose of 20 mg/kg/day for 2 weeks to IL-10(-/-) mice. Severity of colitis, CD4+ T cells in colon lamina propria and proinflammatory cytokine productions were evaluated. Furthermore, intestinal permeability, tight junction (occludin and ZO-1) expressions and distributions, as well as epithelial cell apoptosis, were also assessed. SEW2871 treatment attenuated established colitis associated with decreased CD4+ T cells in colon lamina propria and reduced TNF-α and IFN-γ levels. Moreover, enhanced barrier function, which resulted from ameliorated tight junction (occludin and ZO-1) expressions and suppressed epithelial cell apoptosis, was found to contribute to the therapeutic effects. SEW2871 treatment protects from colitis in IL-10(-/-) mice through reduced epithelial cell apoptosis and improved barrier function. Thus, targeting sphingosine-1-phosphate may represent a new therapeutic approach in Crohn's disease.
authors.affiliation: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Dong
authors.forename: Honggang
authors.initials: H
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Tenghui
authors.initials: T
authors.lastname: Zhang
authors.forename: Lugen
authors.initials: L
authors.lastname: Zuo
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Gong
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Gu
authors.forename: Jieshou
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003092:Colitis / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003424:Crohn Disease / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes / Q000008:administration & dosage* / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000235:genetics
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; C503964:SEW2871; D000081025:Sphingosine-1-Phosphate Receptors; D013876:Thiophenes; D016753:Interleukin-10