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077 DEXTRAN SULPHATE SODIUM-INDUCED COLITIS IN MICE WITH IMPAIRED TNF AND IL-1 SIGNALLING RM Stillie1,3, AW Stadnyk1,2,3 TNF and IL-1 are both implicated in the pathogenesis of inflammatory bowel disease. Paradoxically, TNF-/- mice develop exacerbated dextran sulphate sodium (DSS)-induced colitis compared to wild type (WT) despite the efficacy of anti-TNF therapy. Blocking IL-1, in contrast, does not improve DSS-colitis. Our objectives were to determine the severity of colitis in mice with impaired TNF and IL-1 signaling. We used C57Bl/6 (WT), TNF receptor deficient mice, TNFR1-/- (TNFR1) and TNFR2-/- (TNFR2), and TNFR1/TNFR2-/-, or IL-1R1-/- (IL-1R1) and caspase-1-/- mice (caspase-1). Mice were fed 3% w/v DSS for 5 days and then euthanized at days 7 and/or 12. TNFR1, TNFR2 and TNFR1/TNFR2 mice lost between 9-20% body weight, with the most severe weight loss occurring in TNFR1/TNFR2 mice. By day 12, all groups recovered weight loss. All groups had soft, bloody stools, although the TNFR1/TNFR2 group had severe colonic hemorrhaging with bleeding ulcers in the mid-colon. Histological evaluation of disease severity revealed no significant difference between WT, TNFR1 and TNFR2 mice. TNFR1/TNFR2 mice had the most severe histological damage. In all groups, TNF and IL-1 were upregulated in the mucosa. Caspase-1 mice, which have impaired secretion of IL-1 and IL-18, were found previously to have a less severe form of DSS-induced colitis. In our hands, when IL-1R1 and caspase-1 mice were subjected to the same DSS regimen, it was found that there were no differences compared to WT in all measures of disease severity. Our results show that in agreement with the literature, mice with ablated TNF signalling develop severe DSS-induced colitis, while partial impairment of individual receptors does not affect inflammation compared to WT. Furthermore, impairment of IL-1 does not affect inflammation in these mice. In conclusion, TNFR1 and TNFR2 appear to be redundant in mucosal protection by TNF in DSS-induced colitis, while IL-1 does not seem to play a major role in this model.
1Departments of Microbiology and Immunology, Dalhousie University; 2Department of Pediatrics, IWK Health Centre; 3Dalhousie Inflammation Group, Halifax, Nova Scotia
Funding: Nova Scotia Health Research Foundation, Cancer Research Training Program, Dalhousie Cancer Research Program and Crohn's and Colitis Foundation of Canada