Food and water represent the easiest vehicles to disperse biological agents in this country and individuals have already utilized the food supply as a means for terrorism. Many foodborne pathogens classified as high-priority by the Biodefense and Emerging Infectious Diseases Research Opportunities utilize a common pathway, NF-?B, to exacerbate the host inflammatory response, which dictates disease manifestations. For example, S. typhimurium induces NF-?B-mediated IL-8 secretion from intestinal epithelial cells leading to mucosal inflammation and the clinical manifestations of dysentery, which can be life-threatening. The high frequency and ease of dissemination of foodbome pathggens underscores the need to identify novel pharmacolog!c approaches that may eliminate diseases caused by these agents. Since the production of proinflammatory mediators in response to many of these organisms is regulated by NF-?B, inhibition of microbially-induced NF-?B has the potential to attenuate the host inflammatory response, which if left untreated, may progress to severe complications of enterocolitis and/or systemic illness. One specific constituent that may influence host inflammatory responses to bacteria is the ligand-activated transcription factor PPAR(. PPAR( activation attenuates IL-8 secretion by colonic epithelial cells in vitro and reduces inflammation in murine models of colitis via inhibition of NF-?B. We have similarly shown that PPAR(, activation inhibition NF-?B-mediated IL-8 secretion induced by the gastric pathogen Helicobacter pylori, and attenuates inflammation in two rodent models of H. pylon induced gastritis, underscoring the anti-inflammatory activity of this receptor. These results provide tantalizing evidence that PPAR( activators may represent novel therapies for inflammatory disorders that develop within the gastrointestinal tract. Our hypothesis is that inhibition of NF-?B signaling by PPAR( has the potential to Suppress inflammatory responses and disease induced by foodborne pathogens, Therefore, our Specific Aims are: 1) To determine mechanisms through which microbialiy-induced NF-?B activation is suppressed by PPAR(, in model intestinal epithelia, using S. typhimurium as a prototype organism. 2)To identify and functionally characterize PPAR( target genes and microbially-induced NF-?B-regulated genes that are suppressed by PPAR(, activation using an in vitro model of intestinal epithelial cell inflammation. [unreadable] [unreadable] [unreadable]