Abstract
Mutations that increase susceptibility to inflammatory bowel disease (IBD) have been identified in a number of genes in both humans and mice, but the factors that govern how these mutations contribute to IBD pathogenesis and result in phenotypic presentation as ulcerative colitis (UC) or Crohn disease (CD) are not well understood. In this study, mice deficient in both TNF and IL-10 (T/I mice) were found to spontaneously develop severe colitis soon after weaning, without the need for exogenous triggers. Colitis in T/I mice had clinical and histologic features similar to human UC, including a markedly increased risk of developing inflammation-associated colon cancer. Importantly, development of spontaneous colitis in these mice was prevented by antibiotic treatment. Consistent with the known role of Th17-driven inflammation in response to bacteria, T/I mice had elevated serumTh17-type cytokines when they developed spontaneous colitis and after systemic bacterial challenge via NSAID-induced degradation of the mucosal barrier. Although TNF production has been widely considered to be be pathogenic in IBD, these data indicate that the ability to produce normal levels of TNF actually protects against the spontaneous development of colitis in response to intestinal colonization by bacteria. The T/I mouse model will be useful for developing new rationally-based therapies to prevent and/or treat IBD and inflammation-associated colon cancer and may further provide important insights into the pathogenesis of UC in humans.
Highlights
Human inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn’s disease (CD)
Mice with deletion of the gene that encodes IL-10 were originally reported to spontaneously develop colitis [7], we have found that Il102/2 mice on the C57BL/6 background are resistant to the development of spontaneous colitis when kept free of pathogens such as Helicobacter [8,9]
The work presented here clearly demonstrates that TNF is not required for the development of IBD, at least in Il102/2 mice, a model with genetic, clinical, and histologic features that closely resemble human Crohn disease (CD)
Summary
Human inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn’s disease (CD). The inflammation in UC always involves the rectum and may extend proximally in a continuous fashion to involve the sigmoid, descending colon, or the entire colon (‘‘pancolitis’’). Crypt abcesses and ulceration are common in UC, with inflammation typically limited to the mucosa. CD can involve any part of the gastrointestinal tract, the most common disease patterns involve terminal ileum alone, colon alone, or both terminal ileum and colon. Inflammatory lesions in CD extend deep into the intestinal wall (‘‘transmural’’), may include non-caseating granulomas, and are characteristically separated by uninvolved tissue (‘‘skip lesions’’). Complications of transmural involvement in CD include perforations, formation of large abcesses, and abnormal connections (fistulas) between adjacent bowel loops or the body surface
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