title: Colitogenic role of tumour necrosis factor (TNF) receptors in trinitrobenzene sulphonic acid colitis: TNF-R1 ablation does not affect systemic inflammatory response.
abstract: Tumour necrosis factor (TNF)-α plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF-R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/-) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/-) mice correlated with lower amounts of interleukin (IL)-6, IL-1β, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-γ production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-κB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Dou
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Han
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000139:chemically induced* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004487:Edema / Q000473:pathology; D015870:Gene Expression / Q000235:genetics; D006098:Granulocytes / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D009195:Peroxidase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D000072000:NF-KappaB Inhibitor alpha; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase