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in Clostridium difficile Toxin A-Induced Enteritis1
* Division of Molecular Bioregulation, Cancer Research Institute, and
Department of Bacteriology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan;
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan; and
Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
Clostridium difficile has emerged as the important causative agent of antibiotics-associated pesudomembranous colitis; especially its toxin A is presumed to be responsible for the colitis. We examined the pathophysiological roles of IFN-
in toxin A-induced enteritis using IFN- knockout (KO) mice. When toxin A of C. difficile was injected into the ileal loops of BALB/c wild-type (WT) mice, massive fluid secretion, disruption of intestinal epithelial structure, and massive neutrophil infiltration developed within 4 h after the injection. IFN- protein was faintly detected in some CD3-positive lymphocytes in the lamina propria and submucosa of the ileum of untreated WT mice. On the contrary, at 2 and 4 h after toxin A injection, IFN- protein was detected in infiltrating neutrophils and to a lesser degree in CD3-positive lymphocytes. In the ileum of WT mice, toxin A treatment markedly enhanced the gene expression of TNF-
, macrophage inflammatory protein-1 and -2, KC, and ICAM-1 >2 h after treatment. In contrast, the histopathological changes were marginal, without enhanced fluid secretion in the ileum of toxin A-treated IFN- KO mice. Moreover, toxin A-induced gene expression of TNF-, neutrophil chemotactic chemokines, and ICMA-1 was remarkably attenuated in IFN- KO mice. Furthermore, pretreatment of WT mice with a neutralizing anti-IFN- Ab prevented toxin A-induced enteritis. These observations indicate that IFN- is the crucial mediator of toxin A-induced acute enteritis and suggest that IFN- is an important molecular target for the control of C. difficile-associated pseudomembranous colitis.
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