Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses

• Published in: The Journal of clinical investigation Vol. 98; no. 4; pp. 1010 - 1020
• Main Authors: Berg, D J, Davidson, N, Kühn, R, Müller, W, Menon, S, Holland, G, Thompson-Snipes, L, Leach, M W, Rennick, D
• Format: Journal Article
• Language: English
• Published: United States 15.08.1996
• Subjects: Aging; AIDS/HIV; Animals; Colonic Neoplasms - etiology; Colonic Neoplasms - pathology; Cytokines - biosynthesis; Enterocolitis - etiology; Enterocolitis - pathology; Flow Cytometry; Fluorescent Antibody Technique, Direct; Inflammatory Bowel Diseases - etiology; Inflammatory Bowel Diseases - pathology; Interferon-gamma - physiology; Interleukin-10 - physiology; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Th1 Cells - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI118861

We have characterized the progressive stages of chronic intestinal inflammation that develops spontaneously in specific pathogen-free (SPF) mice with a targeted disruption in the IL-10 gene (IL-10-/-). Our longitudinal studies showed that inflammatory changes first appear in the cecum, ascending and transverse colon of 3-wk-old mutants. As the disease progressed, lesions appeared in the remainder of the colon and in the rectum. Some aged IL-10-/- mice also developed inflammation in the small intestine. Prolonged disease with transmural lesions and a high incidence of colorectal adenocarcinomas (60%) was observed in 6-mo-old mutants. Mechanistic studies have associated uncontrolled cytokine production by activated macrophages and CD4+ Th1-like T cells with the enterocolitis exhibited by IL-10-/- mice. A major role for a pathogenic Th1 response was further suggested by showing that anti-IFNgamma antibody (Ab) treatment significantly attenuated intestinal inflammation in young IL-10-/- mice. When weanlings were treated with IL-10, they failed to develop any signs of intestinal inflammation. Interestingly, IL-10 treatment of adults was not curative but did ameliorate disease progression. Our studies have also shown that inheritable factors strongly influence the disease susceptibility of IL-10-/- mice. In 3-mo-old mutants, intestinal lesions were most severe in IL-10-/- 129/SvEv and IL-10-/- BALB/c strains, of intermediate severity in the IL-10-/- 129 x C57BL/6J outbreds, and least severe in the IL-10-/- C57BL/6J strain.