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

Rijnierse, Anneke, Andries S. Koster, Frans P. Nijkamp, and Aletta D. Kraneveld. TNFis crucial for the development of mast cell-dependent colitis in mice. Am J Physiol Gastrointest Liver Physiol 291: G969–G976, 2006. First published June 22, 2006; doi:10.1152/ajpgi.00146.2006.—Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNFplays a pivotal role in mediating the response. The proinflammatory cytokine TNFis rapidly released by mast cells after degranulation. In the present study, we hypothesized TNFto be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNFMAb 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 TNFlevels in the colon. Anti-TNFMAb 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-TNFMAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNFMAb. 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-TNFMAb. Additionally, dexamethasone treatment could also reduce total TNFlevels in the colon, mast cell numbers, and mast cell activation in both vehicleand DNFB-sensitized mice 72 h after the challenge. These findings suggest that TNFcan play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation.