Gastroenterology

Gastroenterology

Volume 122, Issue 1, January 2002, Pages 94-105
Gastroenterology

Basic Research
Distinct inflammatory mechanisms mediate early versus late colitis in mice*,**

https://doi.org/10.1053/gast.2002.30308Get rights and content

Abstract

Background & Aims: Progression from the acute to chronic phase of inflammatory bowel disease cannot be easily evaluated in patients and has not been characterized in animal models. We report a longitudinal study investigating changes in the mucosal immune response in an experimental model of colitis. Methods: Severity of colitis, body mass, stool consistency and blood content, serum amyloid A, and tissue histology were examined in interleukin (IL)-10–deficient mice over 35 weeks. The corresponding production of IL-12, IL-18, interferon γ, tumor necrosis factor α, IL-4, and IL-13 by lamina propria mononuclear cells in the inflamed intestine was measured. Administration of neutralizing antibody to IL-12 at distinct times during disease progression permitted evaluation of its therapeutic potential. Results: The clinical manifestations and intestinal inflammation delineated an early phase of colitis (10-24 weeks), characterized by a progressive increase in disease severity, followed by a late phase (>25 weeks), in which chronic inflammation persisted indefinitely. Lamina propria mononuclear cells from mice with early disease synthesized progressively greater quantities of IL-12 and interferon gamma, whereas production of both cytokines dramatically declined and returned to pre-disease levels in the late phase of colitis. Consistent with this pattern, neutralizing antibody to IL-12 reversed early, but not late, disease. In contrast, IL-4 and IL-13 production increased progressively from pre- to early to late disease. Conclusions: Colitis that develops in IL-10–deficient mice evolves into 2 distinct phases. IL-12 plays a pivotal role in early colitis, whereas its absence and the synthesis of IL-4 and IL-13 in late disease indicate that other immune mechanisms sustain chronic inflammation.

GASTROENTEROLOGY 2002;122:94-105

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.

    **

    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.).

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