Role of TNF-alpha in muscularis inflammation and motility disorder in a TNBS-induced colitis model: clues from TNF-alpha-deficient mice.
Macroscopic and histological analysis revealed that the colonic inflammation induced by 2,4,6-trinitrobenzenesulphonic acid (TNBS) was of lower grade in tumour necrosis factor-alpha (TNF-alpha)(-/-) mice than in wild-type mice. Myeloperoxidase activity, an indicator of neutrophilic infiltration, was also low in both the mucosal and smooth muscle layer of the TNF-alpha(-/-) mouse colon. After the induction of inflammation with TNBS, the levels of proinflammatory cytokines, such as TNF-alpha, interleukin-1beta and interleukin-6, were elevated both in the inflamed mucosa and muscle layers in the wild-type mice; however, the productions of these cytokines were greatly reduced in the TNF-alpha(-/-) mouse colon. The contractions of isolated colonic smooth muscle strips induced by several stimulatory agents were significantly decreased after treatment with TNBS in wild-type mice; however, these contractions were scarcely affected in TNF-alpha(-/-) mice. Finally, using the organ culture method, we found that TNF-alpha directly (independent of mucosal inflammation) disturbs the smooth muscle function. These results suggest that TNF-alpha plays an essential role not only in mucosal inflammation but also in muscularis inflammation in the colon of mice with TNBS-induced colitis, and that TNF-alpha directly induces motor dysfunctions by acting on the smooth muscle.
Kinoshita
K
K
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Hori
M
M
Fujisawa
M
M
Sato
K
K
Ohama
T
T
Momotani
E
E
Ozaki
H
H
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase