Increasing evidence exists that intestinal epithelial cells are important regulators of the development of immunity. Elucidation of these mechanisms will be essential to advance understanding of the pathophysiology of inflammatory bowel disease and other diseases of the intestinal mucosa. However, the understanding of the communication between intestinal epithelial cells and intestinal lymphocytes in the healthy and diseased intestinal mucosa is incomplete. Preliminary data has demonstrated that intestinal epithelial cells express cytokine receptors which share the common gamma-c chain, including the receptor for IL-2. In addition, preliminary findings have identified the newly described cytokine IL-IS as a potential mediator between intestinal epithelial cell function and the regulation of the intestinal immune system. IL- 15 exhibits potent overlapping functional roles in the immune system with IL-2. Both are thought to signal through the same receptor complex including the common gamma-c receptor subunit and the IL-2 receptor (3 subunit. The ability of intestinal epithelial cells to express IL-IS in conjunction with the expression of functional IL-2 receptors may constitute an important ligand- receptor system that may integrate intestinal epithelial cells into the mucosal immune system. The goal of this study is the determination of the intestinal expression and function of IL-15 in order to provide insight into a previously unrecognized pathway of epitheliallymphocyte interaction in intestinal mucosa. The overall hypothesis is that: 1) The IL-15/IL-2 receptor system may be crucial for the regulation of intestinal epithelial cell function, 2) IL-15 may be an important epithelial cell derived regulator of intestinal lymphocytes, and 3) The interaction of intestinal epithelial cells and intestinal lymphocytes through the IL-15/IL-2 receptor system may be pivotal for the initiation and/or perpetuation of IBD. These issues will be addressed by the following specific aims: 1. To define the expression of IL-15 in the intestinal mucosa. 2. To determine the regulation of intestinal epithelial cell function by IL-15. 3. To assess the function of IL-15 for the regulation of intraepithelial lymphocytes. 4. To determine the role of IL-15 in intestinal inflammation. Collectively, these studies will help to understand how epithelial cells are integrated into the regulation of the immune response in intestinal inflammation and healing.
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