FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice

AIM： To investigate the effects of FR167653 on the development of dextran sulfate sodium （DSS）-induced colitis in mice. METHODS： BALB/c mice were fed rodent chow containing 3.5% （wt/wt） DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 （30 mg/kg per day）. The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4^＋ T cell and F4/80^＋ macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR. RESULTS： The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicletreated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration （CD4 T cells and F4/80 macrophages）, and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） were found to be markedly reduced in FR167653-treated DSS mice. CONCLUSION： Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase （MAPK）-mediated proinflammatory cytokine induction in host defense mechanisms.