Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory disease that arises through unknown genetic, environmental, and bacterial origins. Ulcerative colitis (UC) and Crohn's disease (CD) are the two main forms of IBD, and their incidence is increasing in industrialized countries. Further, IBD is a significant risk factor for the development of colon cancer. Though the specific determinants remain elusive, persistent inflammation is believed to play a significant role in colon cancer carcinogenesis. To better define the molecular mechanisms linking colitis to the identity of disease biomarkers, we performed a translational comparison of protein expression and protein damage products in mouse and human IBD. Helicobacter hepaticus-infected Rag2-/- mice emulate many aspects of human IBD, and our recent work with this model highlights the importance of neutrophils in the pathology of colitis and colon cancer. Analysis of neutrophil- and macrophage-derived damage products revealed accumulation of 3-chlorotyrosine (CTyr) and 3-nitrotyrosine (NTyr) in inflamed mice colons that increased with disease duration. These results were further corroborated in mouse studies by histological evaluation, which demonstrated strong infiltration of neutrophils and macrophages to the site of inflammation. Human studies revealed an increase in CTyr in the colon of UC and CD tissues relative to serum levels. The nucleic acid chlorination damage product, 5-chloro-2′-deoxycytidine (5-Cl-dC), was quantified in human colon and found to be present at similar levels to that of inflamed mice colons. Multivariate analysis of these markers along with serum proteins and cytokines revealed a general signature of activated innate immunity in human IBD. UC sera were strongly suggestive of neutrophil activity while CD and mouse sera were suggestive of macrophage and neutrophil activity. These data point to innate immunity as a major determinant of serum and tissue profiles and provide insight into disease activity in IBD.
Citation Format: Charles G. Knutson, Aswin Mangerich, Yu Zeng, Arkadiusz R. Raczynski, Rosa G. Liberman, Pilsoo Kang, Wenjie Ye, Guanyu Gong, Erin Prestwich, Kun Lu, John S. Wishnok, Joshua R. Korzenik, Gerald N. Wogan, James G. Gox, Peter C. Dedon, Steven R. Tannenbaum. Features of innate immunity dominate serum and tissue protein and cytokine profiles in both mouse and human inflammatory bowel disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2885. doi:10.1158/1538-7445.AM2013-2885