FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice.
OBJECTIVE
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-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were found to be markedly reduced in FR167653-treated DSS mice.


CONCLUSIONS
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.
Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Japan.
Takashi
T
Nishimura
Akira
A
Andoh
Atsushi
A
Nishida
Makoto
M
Shioya
Yuhsuke
Y
Koizumi
Tomoyuki
T
Tsujikawa
Yoshihide
Y
Fujiyama
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003092:Colitis / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011720:Pyrazoles / Q000633:toxicity*; D011725:Pyridines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000943:Antigens, Differentiation; C104334:FR 167653; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D016264:Dextran Sulfate; D048051:p38 Mitogen-Activated Protein Kinases