Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.
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.
Berg
D J
DJ
Department of Immunology and Molecular Biology, DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, California 94304, USA.
Davidson
N
N
Kühn
R
R
Müller
W
W
Menon
S
S
Holland
G
G
Thompson-Snipes
L
L
Leach
M W
MW
Rennick
D
D
D000375:Aging; D000818:Animals; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D004760:Enterocolitis / Q000209:etiology* / Q000473:pathology; D005434:Flow Cytometry; D019085:Fluorescent Antibody Technique, Direct; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology*
D016207:Cytokines; D016753:Interleukin-10; D007371:Interferon-gamma