Control of Intestinal Inflammation and Colon Cancer by Novel Genetic and Cytokine-Mediated Pathways

Chronic intestinal inflammation is a colorectal cancer risk factor. Our group has characterized a model of chronic colitis-induced colon cancer that involves infection of 129/SvEv.Rag^-/- mice with Helicobacter hepaticus (Hh). We previously described a congenic line, termed R17.Rag^-/-, that harbours a 1.7Mb locus of B6 origin on chromosome 3 and is resistant to Hh-induced colitis and colon cancer. Tumourigenesis in this model is dependent on interleukin (IL)-22. In addition to controlling chronic colitis, this locus regulates acute inflammation following Hh infection, involving pronounced recruitment of neutrophils and inflammatory monocytes within 2–5 days following infection. R17.Rag^-/- mice are also protected from acute colitis, likely due to an enhanced ability to produce IL-10 in colon lamina propria macrophages and dendritic cells. Blockade of the IL-10 receptor during Hh colonization causes R17.Rag^-/- mice to phenocopy the inflammatory pathology of 129/SvEv.Rag^-/- animals. We are currently investigating mechanisms to account for the IL-10 deficiency observed in 129 mice. Genetic complementation studies have excluded several genes in the susceptibility locus as candidate disease-regulators, leaving several possibilities including Alpk1, which harbours several nonsynonymous polymorphisms between 129 and R17 mice, is highly expressed by disease-susceptible animals, and is associated with human inflammatory bowel disease and colon cancer.