With more than one million Americans affected, inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn's disease, causes significant morbidity and can progress to colon cancer. While multiple predisposing factors have been identified, the cause or trigger for IBD remains unknown. Current treatment regimens for IBD are selected from an assortment of immunosuppressive agents, which can be complicated by multiple side effects and expense. In the search for new therapeutic options, including studies in vitro, in mouse models, and in a prospectively collected cohort of adult patients with UC, our human serum profiling data indicate that eotaxin-1 may be a biomarker of disease activity in UC. Eotaxin-1 (CCL11) is a chemoattractant for eosinophils. When the cytokine and chemokine profiles in this cohort of 40 controls and 137 UC patients were defined, there were 13 tissue cytokines and chemokines that were significantly elevated in the UC versus control patients, but out of a panel of 42 analytes, there were only 3 that were elevated in the serum: eotaxin-1, G-CSF, and GM-CSF. Of these, eotaxin-1 was the only analyte increased in both serum and tissue at all levels of disease severity. Increased eotaxin-1 has been shown in pediatric UC tissues, and has been linked to eosinophilic inflammation, but has not been previously investigated in a large, prospective adult UC cohort. Due to the novelty of this observation, studies of the role of eotaxin-1 in mouse models of colitis and colitis-associated carcinogenesis are the focus of this proposal. Along with the increased serum and tissue eotaxin-1, there is a significant increase in colonic tissue eosinophils in UC patients versus controls, and eosinophil counts correlated with tissue eotaxin-1 levels. Eotaxin-1 has been shown to be increased in dextran sulfate sodium (DSS) induced colitis by my collaborator, and we now show for the first time that eotaxin-1 is upregulated in: 1) Citrobacter rodentium-induced colitis tissues;2) T cell transfer-induced colitis tissues;3) tumor induced in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis;and 4) macrophages or colonic epithelial cells activated with C. rodentium. However, eotaxin-1 is not increased in mouse Helicobacter pylori-induced gastritis tissues, indicating that this is not a non specific component of inflammation. Hypothesis: Eotaxin-1 is a key mediator of colitis and colitis-associated carcinogenesis via effects on macrophages and epithelial cells.
The Specific Aims for this project are: 1. To determine the role of eotaxin-1 in the modulation of experimental colitis. We will utilize the C. rodentium infection model of colitis that involves immune activatio and the T cell transfer model of colitis that involves immune activation and epithelial damage. We will compare wild-type (WT) and eotaxin1-/- mice in the C. rodentium model, as well as eotaxin1+/+Rag2-/- and eotaxin1-/-Rag2-/- mice, with and without adoptive transfer of CD4+CD45RBhi effector T cells in the T cell transfer model. In each model of colitis the following will be assessed: clinical parameters, the colonic and systemic innate immune response focusing on macrophage phenotype and function, as well as epithelial function. 2. To determine the role of eotaxin-1 in the modulation of chronic colitis and colitis-associated carcinogenesis (CAC). Our preliminary data shows for the first time that colitis-associated tumors in the AOM-DSS model have increased eotaxin-1 levels. We will utilize the AOM-DSS model in WT and eotaxin1-/- mice to establish whether modification of the inflammatory response caused by deletion of eotaxin-1 can decrease the risk for CAC. In both chronic colitis (mice treated with multiple cycles of DSS) and colitis-associated tumorigenesis (mice treated with AOM followed by multiple cycles of DSS) the following will be assessed: clinical parameters including tumor size and multiplicity, colonic and systemic innate immune responses focusing on macrophage phenotype and function, as well as epithelial function, including in tumor and adjacent non-tumor tissues. These studies will provide new mechanistic insights into the role of eotaxin-1 in IBD and associated carcinogenesis.
Inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn's disease, affects more than 1.4 million Americans and is characterized by repeated episodes of increased symptoms that decrease quality of life and increase the risk for colorectal cancer (CRC). The cause of IBD remains unknown leading to difficulty in finding treatments that reliably lead to remission. IBD accounted for more than 121,000 VA healthcare system hospitalizations from 1975 to 2006, about 1 of every 200 admissions. IBD patients require chronic therapy with frequent office visits and repeated admissions. Additionally, CRC occurs in Veterans with IBD at a younger age and more proximal location compared to Veterans without IBD. The link between IBD and CRC is firmly established, and a 2001 meta-analysis calculated the cumulative probabilities of developing CRC in UC as 2% by 10 years, 8% by 20 years, and 18% by 30 years. There is an ongoing need to develop therapies that ameliorate morbidity and decrease CRC, and we aim to establish eotaxin-1 as one such target.
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