Basic ResearchDistinct inflammatory mechanisms mediate early versus late colitis in mice*,**
Section snippets
Animals
IL-10–deficient (IL-10−/−) and wild-type (IL-10+/+) mice on a C57BL/10 background were obtained from Dr. Alan Sher (Bethesda, MD) with permission from Dr. Werner Muller (Frankfurt, Germany).11 All mice, negative for intestinal Helicobacter hepaticus, were kept in specific pathogen–free housing and fed autoclaved mouse chow and water. The Institutional Animal Care and Use Committee approved all experimental protocols.
Antibodies and reagents
Neutralizing antibody to IL-12 (C17.15), obtained from G. Trinchieri, Wistar
Mucosal production of IL-12 and IFN-γ increases in colitic mice
IL-10+/+ and IL-10−/− mice gained weight similarly and steadily for the first 10 weeks of life. At 10 weeks of age, which is the time of onset of intestinal inflammation, IL-10−/− mice failed to gain additional weight, reaching a plateau at 22 g, whereas the total body mass of their wild-type littermates increased to greater than 30 g. Both histologic evaluation of their colon and clinical observations of loose stools and occult fecal blood revealed that the inflammation steadily worsened over
Discussion
The molecular mechanisms that initiate inflammation are distinct from those in chronic inflammatory disease. The results of this study are the first to demonstrate immunologic and therapeutic differences between early and late inflammation in experimental IBD. Our studies in the IL-10–deficient mouse model of colitis confirm that aberrant mucosal IL-12 production, in conjunction with a massive influx of lymphocytes and increased IFN-γ, initiates and perpetuates mucosal inflammation in the early
Acknowledgements
The authors thank C. Fiocchi for his advice, S. Latifi and R. Jump for their technical support and encouragement, and M. O'Riordan and A. Leite for statistical analyses.
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Address requests for reprints to: Alan D. Levine, Ph.D., Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106-4952. e-mail: [email protected]; fax: (216) 368-1674.
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This work is supported by a grant from the Crohn's and Colitis Foundation of America, Inc. and DK-57756 from the National Institutes of Health (to A.D.L.).