Role of TNF‐ α in muscularis inflammation and motility disorder in a TNBS‐induced colitis model: clues from TNF‐ α ‐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‐ α (TNF‐ α ) −/− 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‐ α −/− mouse colon. After the induction of inflammation with TNBS, the levels of proinflammatory cytokines, such as TNF‐ α , interleukin‐1 β 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‐ α −/− 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‐ α −/− mice. Finally, using the organ culture method, we found that TNF‐ α directly (independent of mucosal inflammation) disturbs the smooth muscle function. These results suggest that TNF‐ α 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‐ α directly induces motor dysfunctions by acting on the smooth muscle.