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-IFN gamma 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.