Ulcerative colitis and Crohn's disease, collectively referred to as inflammatory bowel disease (IBD), are immunologically mediated disorders characterized by an unrestrained immune response with increased production of a number of proinflammatory cytokines. Our hypothesis is that ulcerative colitis, Crohn's disease and their complications such as fibrosis and extraintestinal inflammation, arise from an overly aggressive immunologic reaction to ubiquitous luminal bacterial constituents. This injurious reaction is a result of failure of the genetically susceptible host to appropriately downregulate the inflammatory response. The normal host when stimulated with a variety of bacterial polymers and injurious agents appropriately suppresses inflammation through production of immunosuppressive molecules including IL-1 receptor antagonist (IL-1ra) and I-kappa-B, an intracytoplasmic protein that inhibits the activity of nuclear factor kappa-B (NF-kappa-B). Dr. Haskell has cloned I-kappa-B and an intracellular form of IL-1ra. In preliminary studies we have demonstrated that patients with Crohn's disease have a decreased IL- 1ra/IL-1 ratio, suggesting that these patients have defective downregulation of the inflammatory response. We will investigate this hypothesis with the following specific aims: 1. Measure the relative balance and tissue localization of IL-1 (intracellular and secreted isoforms), IL-1ra, an I-kappa-B in tissues of patients with well characterized ulcerative colitis, Crohn's disease, self-limited infectious colitis and normal controls. 2. Examine regulation of inhibitory molecules in tissues from IBD and control patients in response to environmentally relevant bacterial products and immunoregulatory cytokines. 3. Determine whether overexpression of inhibitory molecules alters regulation of proinflammatory cytokines and mediators in stimulated intestinal cell lines. These studies measure the balance of pro inflammatory and inhibitory molecules in mucosal biopsies from patients and controls and use a mucosal explant system for in vitro stimulation with bacterial products and cytokines. Overexpression of inhibitory molecules in intestinal epithelial and smooth muscle cell lines will be performed by transfection of IL-1ra and I-kappa-B genes. Our ultimate goal is to treat and prevent IBD by augmenting endogenous inhibitory pathways either by gene therapy or pharmacologic stimulation.
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