The Role of IL-25 in Colitis-Associated Colon Cancer and Pulmonary Inflammation.

摘要

Epithelial cells located at mucosal barrier surfaces act as our front-line of defense against environmental toxins, pathogens, and helminth infections. Activation of pattern recognition receptors (PRRs) on epithelial cells stimulates them to produce IL-25, IL-33, and TSLP. These three cytokines, acting individually and/or in cooperation with one another, are capable of initiating and maintaining type-2 inflammation. There remain many unanswered questions in regard to the specific cell types IL-25 acts upon to produce pulmonary inflammation. In addition, whether the roles for IL-25, IL-33, and TSLP are interdependent and/or redundant has been largely unexplored. In this study, we selectively inhibited IL-25 signaling on CD4+ cells, monocyte/macrophage populations, and CD11c+ dendritic cells by deleting its receptor, IL-17RB. In each of these systems, we found IL-25 was able to generate type-2 inflammation despite the lack of direct signaling in any of these cells. Additionally, when IL-33 and TSLP signaling (individually and in combination) were deleted, IL-25 was still capable of initiating an effective inflammatory response. Collectively, these results indicate a multifaceted role for IL-25 that is not dependent on its direct signaling through CD4+ cells, monocytes/macrophages, or dendritic cells to create a response, nor is it dependent on IL-33 or TSLP. These studies are the first of their kind to look at IL-25 induced inflammation by deleting its receptor on specific cell types, and in the absence of other epithelial cytokines.;Chronic inflammation within the gastrointestinal tract results in an increased risk for developing colorectal cancer. Epithelial cell production of IL-25 within the colon is critical for protection from parasites, but can also be pathogenic in the context of inflammatory bowel diseases and allergy. Whether IL-25 is involved in the progression from inflammation to cancer is still largely unexplored. Using a well-established murine model for colitis-induced colon cancer; we aimed to determine the role of IL-25 in this process. We found that acute antibody mediated IL-25 blockade resulted in greater tumor burdens than did treatment with isotype control. Histologically, alpha-IL-25 treated mice had increased colitis scores compared to mice receiving isotype control antibody, as well as decreased eosinophilia. This is the first study to explore the therapeutic potential of using an IL-25 blocking antibody during a chronic inflammatory setting. Taken together, these data suggest that IL-25 plays an inhibitory role in the growth and development of colonic tumors.