Role of TNF receptors, TNFR1 and TNFR2, in dextran sodium sulfate-induced colitis.
BACKGROUND
In this study we determined the consequence of the absence of each TNF receptor, TNFR1 or TNFR2, in the dextran sulfate sodium (DSS) model of colitis.


METHODS
Wildtype (WT), TNFR1(-/-) and TNFR2(-/-) mice were fed 3% w/v DSS in drinking water for 5 days followed by 2 (day 7) or 7 (day 12) days of tap water.


RESULTS
The colons from untreated TNFR1(-/-) and TNFR2(-/-) mice were histologically normal. Following DSS, all strains became inflamed. TNFR1(-/-) mice had a more severe clinical score at days 8 and 9 compared to WT and TNFR2(-/-) mice despite similar histopathological damage in their colons. The more severe clinical score was associated with a reduced macrophage infiltration into the colonic mucosa. TNFR2(-/-) mice showed increased indicators of disease including increased colon weight, a shrunken cecum, and an increased number of ulcers compared to TNFR1(-/-) and WT strains at day 7. Mucosal levels of TNFR2 were elevated in colitic mice compared to uninflamed controls, with no difference between strains on day 7 but on day 12, unlike WT mice, levels were reduced in TNFR1(-/-) mice. There was no difference in the number of TUNEL-positive apoptotic colonic epithelial cells between strains, nor in total cleaved caspase 3 levels between strains, measured by Western blot of colon homogenates.


CONCLUSIONS
While deficiency of either receptor contributes to some measures of DSS colitis, the histopathological scores are similar, indicating that TNF receptors either do not play a major role or are redundant in the pathology associated with DSS colitis.
Stillie
RoseMarie
R
Department of Microbiology and Immunology, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada.
Stadnyk
Andrew W
AW
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*
D061945:Caspase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D016264:Dextran Sulfate; D020169:Caspases