TNF-alpha is crucial for the development of mast cell-dependent colitis in mice.
Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNF-alpha plays a pivotal role in mediating the response. The proinflammatory cytokine TNF-alpha is rapidly released by mast cells after degranulation. In the present study, we hypothesized TNF-alpha to be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNF-alpha MAb was studied on colonic hypersensitivity in mice induced by a skin application of dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene 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-alpha levels in the colon. Anti-TNF-alpha 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-alpha MAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNF-alpha 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-alpha MAb. Additionally, dexamethasone treatment could also reduce total TNF-alpha 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-alpha can play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation.
Rijnierse
Anneke
A
Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. a.rijnierse@pharm.uu.nl
Koster
Andries S
AS
Nijkamp
Frans P
FP
Kraneveld
Aletta D
AD
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D004139:Dinitrofluorobenzene; D007150:Immunohistochemistry; D008297:Male; D008407:Mast Cells / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D004139:Dinitrofluorobenzene