Colorectal cancer (CRC) is the 2ndmost common cause of cancer death in developed countries, despite advances in surgery and chemotherapy. The association of CRC with chronic inflammation was described previously. IL-1 is a major pro-inflammatory upstream cytokine, which initiates and propagates inflammation. In this study our task has been to establish the role of IL-1 incolon carcinogenesis. For this aim, we have used a series of mice deficient in molecules of the IL-1 family, as follows: IL-1a, IL-1β and IL-1Ra KO mice, in which we have established models of experimental chronic colitis as well as the AOM/DSS model of colon carcinogenesis. In the model of chronic colitis, we found that mice deficient in IL-1Ra, which have an attenuated levels of both agonistic IL-1 molecules (IL-1α and IL-1β), have a severe form of disease and in many cases also develop spontaneous adenomas. This phenomenon was not observed in control, IL-1α-or IL-1β-deficient mice after chronic colitis. Tumor development in IL-1Ra KO mice was associated with increased infiltration of myeloid suppressor cells and also with a high angiogenic response in colon tissues, from the early phases of the disease. After induction of CRC by AOM/DSS, tumors were observed in all groups of mice, but in mice deficient in IL-1α and IL-1β fewer tumors appeared, as compared to control mice. In contrast, in mice deficient in IL-1Ra the number of invasive adenocarcinomas was increased. Our findings suggest a significant role of overexpression of the IL-1 molecules in CRC development.Thus, anti-inflammation therapy by IL-1 neutralizationat the early stages of colon inflammationhas the potential to prove beneficial, as this may prevent the entire pro-inflammatory cascade that is involved in CRC development.
