title: Tumor necrosis factor-α and Muc2 mucin play major roles in disease onset and progression in dextran sodium sulphate-induced colitis.
abstract: The sequential events and the inflammatory mediators that characterize disease onset and progression of ulcerative colitis (UC) are not well known. In this study, we evaluated the early pathologic events in the pathogenesis of colonic ulcers in rats treated with dextran sodium sulfate (DSS). Following a lag phase, day 5 of DSS treatment was found clinically most critical as disease activity index (DAI) exhibited an exponential rise with severe weight loss and rectal bleeding. Surprisingly, on days 1-2, colonic TNF-α expression (70-80-fold) and tissue protein (50-fold) were increased, whereas IL-1β only increased on days 7-9 (60-90-fold). Days 3-6 of DSS treatment were characterized by a prominent down regulation in the expression of regulatory cytokines (40-fold for IL-10 and TGFβ) and mucin genes (15-18 fold for Muc2 and Muc3) concomitant with depletion of goblet cell and adherent mucin. Remarkably, treatment with TNF-α neutralizing antibody markedly altered DSS injury with reduced DAI, restoration of the adherent and goblet cell mucin and IL-1β and mucin gene expression. We conclude that early onset colitis is dependent on TNF-α that preceded depletion of adherent and goblet cell mucin prior to epithelial cell damage and these biomarkers can be used as therapeutic targets for UC.
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, Gastrointestinal Research Group, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Poonam
authors.initials: P
authors.lastname: Dharmani
authors.forename: Pearl
authors.initials: P
authors.lastname: Leung
authors.forename: Kris
authors.initials: K
authors.lastname: Chadee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism; D007124:Immunoenzyme Techniques; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C524626:Muc2 protein, mouse; D055262:Mucin-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016264:Dextran Sulfate