Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastro-intestinal tract and tumor necrosis factor alpha (TNF) plays a pivotal role in mediating the response. The pro-inflammatory 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 skin application of dinitrofluorobenzene (DNFB) followed by intrarectal challenge with dintrobenzene sulfonic acid (DNS). Features of the colonic hypersensitivity response include 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 72h after challenge. The number of colonic patches and total tissue damage score were reduced by anti-TNF MAb treatment in DNFB-sensitization 72h after 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 reduction of diarrhea, cellular infiltration and total tissue damage score in the same extent as anti-TNF MAb. Additionally, dexamethasone treatment could also reduce total TNF levels in the colon, mast cell number and mast cell activation in both vehicle- and DNFB-sensitized mice 72h after 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.