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.
Highlights
Ulcerative colitis (UC) is a gastrointestinal disorder characterized by inflammatory response and mucosal damage [1]
Intestinal epithelial barrier is maintained by intracellular junctional complexes, such as tight junctions (TJ), adherent junctions, and desmosomes [4]
Previous investigations by freeze fracture electron microscopy demonstrated a reduction of TJ strands in UC, which is considered to be a possible cause of barrier dysfunction [4,11]
Summary
Ulcerative colitis (UC) is a gastrointestinal disorder characterized by inflammatory response and mucosal damage [1]. Uncontrolled local inflammation disrupts the epithelial lining, resulting in mucosal edema and ulceration, and even crypt abscess in the bowel wall [2]. The intestinal barrier is constituted of an intact layer of epithelial cells, act as the gateway restricting uncontrolled entry of luminal antigens [3]. Claudins, which is the major integral membrane proteins forming the continuous TJ strands, interact in a tissue-specific manner to form a charge-selective and size-selective barrier, and predominantly contribute to epithelial barrier function [6,7,8,9,10]. The disrupted morphology of TJ is often the result of changes in TJ protein expression [4]. Only a few researches concert on the expression patterns of claudins in UC, and the results are still controversial, needs further investigation
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