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INFLAMMATION/IMMUNITY/MEDIATORS

TNF- is crucial for the development of mast cell-dependent colitis in mice

Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Submitted 30 March 2006 ; accepted in final form 19 June 2006

Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNF- plays a pivotal role in mediating the response. The proinflammatory cytokine TNF- is rapidly released by mast cells after degranulation. In the present study, we hypothesized TNF- to be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNF- MAb was studied on colonic hypersensitivity in mice induced by a skin application of dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dintrobenzene sulfonic acid. Features of the colonic hypersensitivity response included diarrhea, mast cell infiltration and activation, infiltration of inflammatory cells in the colon, colonic patch hypertrophy, and increased mast cell-derived TNF- levels in the colon. Anti-TNF- MAb could effectively abrogate diarrhea in DNFB-sensitized mice 72 h after the challenge. The numbers of colonic patches and total tissue damage scores were reduced by anti-TNF- MAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNF- MAb. Treatment with the corticosteroid dexamethasone, a frequently used therapeutic treatment in IBD, resulted in a reduction of diarrhea, cellular infiltration, and total tissue damage scores to the same extent as anti-TNF- MAb. Additionally, dexamethasone treatment could also reduce total TNF- levels in the colon, mast cell numbers, and mast cell activation in both vehicle- and DNFB-sensitized mice 72 h after the challenge. These findings suggest that TNF- can play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation.

inflammatory bowel disease; tumor necrosis factor-; dexamethasone; dinitrofluorobenzene

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