Basic Research
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Oct 14, 2008; 14(38): 5851-5856
Published online Oct 14, 2008. doi: 10.3748/wjg.14.5851
FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice
Takashi Nishimura, Akira Andoh, Atsushi Nishida, Makoto Shioya, Yuhsuke Koizumi, Tomoyuki Tsujikawa, Yoshihide Fujiyama
Takashi Nishimura, Akira Andoh, Atsushi Nishida, Makoto Shioya, Yuhsuke Koizumi, Tomoyuki Tsujikawa, Yoshihide Fujiyama, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan
Author contributions: Nishimura T performed research; Andoh A wrote the paper; Nishida A, Shioya M, Koizumi Y, Tsujikawa T, and Fujiyama Y designed research.
Correspondence to: Akira Andoh, MD, Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan. andoh@belle.shiga-med.ac.jp
Telephone: +81-77-5482217 Fax: +81-77-5482219
Received: April 21, 2008
Revised: July 5, 2008
Accepted: July 12, 2008
Published online: October 14, 2008
Abstract

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 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-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.

Keywords: p38; Inflammatory bowel disease; Cytokine; Experimental colitis; Tumor necrosis factor-α