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

To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.

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.

The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated 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-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were found to be markedly reduced in FR167653-treated DSS mice.

Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1beta and TNF-alpha expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.