Project Summary/Abstract The overarching goal of the proposed research is to elucidate the initiating mechanisms in the development of cancer-prone chronic inflammation for cancer prevention and therapy. Chronic inflammatory diseases, such as chronic dermatitis, pancreatitis, colitis and hepatitis, are major risk factors for cancer. In addition, a tumor- promoting immune environment, which resembles chronic inflammation, is a key driver of cancer development across the majority of cancer types. By studying the mediators of the transition from acute to chronic inflammation, we have demonstrated that interleukin (IL)-33 cytokine is a key initiator of chronic inflammation that eventually leads to cancer development in the skin, colon and pancreas. Importantly, we have recently discovered that the nuclear function of IL-33 within the epithelial cells plays an essential role in cancer development in chronic skin and pancreas inflammation. To develop an effective strategy to suppress cancer- prone chronic inflammation, we will focus on the mechanism that blocks the initiating steps in the development of a cancer-prone chronic inflammation. Founded on our innovative discovery that IL-33 is an essential initiator of cancer-prone chronic inflammation, we aim to determine the mechanism of IL-33 induction in tissues exposed to inflammatory insults and to develop a novel therapeutic approach to inhibit IL-33 expression for cancer prevention and therapy. To accomplish this, we will use novel mouse models and clinical samples to (1) determine the mechanism of IL-33 induction in chronic inflammation triggered by chemical agents, (2) investigate the role of IL-33 in cancer-prone chronic inflammation associated with a viral infection, and (3) study inhibitor of IL-33 that can block chronic inflammation and the subsequent cancer development. The outcomes of our research will establish a fundamental pathway to suppress chronic inflammation-associated cancer and provide the means to prevent cancer progression and recurrence.