title: CXCR4 antagonist AMD3100 modulates claudin expression and intestinal barrier function in experimental colitis.
abstract: Ulcerative colitis is a gastrointestinal disorder characterized by local inflammation and impaired epithelial barrier. Previous studies demonstrated that CXC chemokine receptor 4 (CXCR4) antagonists could reduce colonic inflammation and mucosal damage in dextran sulfate sodium (DSS)-induced colitis. Whether CXCR4 antagonist has action on intestinal barrier and the possible mechanism, is largely undefined. In the present study, the experimental colitis was induced by administration of 5% DSS for 7 days, and CXCR4 antagonist AMD3100 was administered intraperitoneally once daily during the study period. For in vitro study, HT-29/B6 colonic cells were treated with cytokines or AMD3100 for 24 h until assay. DSS-induced colitis was characterized by morphologic changes in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced, and the disease activity index was also significantly decreased. Increased intestinal permeability in DSS-induced colitis was also significantly reduced by AMD3100. The expressions of colonic claudin-1, claudin-3, claudin-5, claudin-7 and claudin-8 were markedly decreased after DSS administration, whereas colonic claudin-2 expression was significantly decreased. Treatment with AMD3100 prevented all these changes. However, AMD3100 had no influence on claudin-3, claudin-5, claudin-7 and claudin-8 expression in HT-29/B6 cells. Cytokines as TNF-α, IL-6, and IFN-γ increased apoptosis and monolayer permeability, inhibited the wound-healing and the claudin-3, claudin-7 and claudin-8 expression in HT-29/B6 cells. We suggest that AMD3100 acted on colonic claudin expression and intestinal barrier function, at least partly, in a cytokine-dependent pathway.
authors.affiliation: Department of Gastroenterology and Hepatology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China. xiaxm2000@hotmail.com
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Xia
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Wang
authors.forename: Ju
authors.initials: J
authors.lastname: Zhou
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Hu
authors.forename: Su-Wen
authors.initials: SW
authors.lastname: Li
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Zou
mesh_terms: D000818:Animals; D001596:Benzylamines; D015153:Blotting, Western; D057167:Claudins / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology*; D000080027:Cyclams; D005260:Female; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D057167:Claudins; D000080027:Cyclams; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
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