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INFLAMMATION/IMMUNITY/MEDIATORS

Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells

¹Intestinal Disease Research Program, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ²Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Submitted 13 February 2006 ; accepted in final form 16 May 2006

Mucosal changes in inflammatory bowel disease (IBD) are characterized by ulcerative lesions accompanied by a prominent infiltrate of inflammatory cells including lymphocytes, macrophages, and neutrophils and alterations in 5-hydroxytryptamine (5-HT)-producing enterochromaffin (EC) cells. Mechanisms involved in recruiting and activating these cells are thought to involve a complex interplay of inflammatory mediators. Studies in clinical and experimental IBD have shown the upregulation of various chemokines including monocyte chemottractant protein (MCP)-1 in mucosal tissues. However, precise information on the roles of this chemokine or the mechanisms by which it takes part in the pathogenesis of IBD are not clear. In this study, we investigated the role of MCP-1 in the development of hapten-induced experimental colitis in mice deficient in MCP-1. Our results showed a significant reduction in the severity of colitis both macroscopically and histologically along with a decrease in mortality in MCP-1-deficient mice compared with wild-type control mice. This was correlated with a downregulation of myeloperoxidase activity, IL-1, IL-12p40, and IFN- production, and infiltration of CD3⁺ T cells and macrophages in the colonic mucosa. In addition, we observed significantly lower numbers of 5-HT-expressing EC cells in the colon of MCP-1-deficient mice compared with those in wild-type mice after dinitrobenzenesulfonic acid. These results provide evidence for a critical role of MCP-1 in the development of colonic inflammation in this model in the context of immune and enteric endocrine cells.

monocyte chemottractant protein-1; dinitrobenzenesulfonic acid; CD3-positive cells; 5-hydroxytryptamine; serotonin

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