Regulation of Pro- and Anti-Inflammatory Gene Expression in Intestinal Epithelial Cells by Colonic Bacteria

  • Kaetzel, Charlotte (PI)

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Inappropriate responses to colonic bacteria can lead to the development of inflammatory bowel disease (IBD) in genetically susceptible individuals. Intestinal epithelial cells (lEe) act at the interface between the mnate and acquired immune responses to bacteria in the gastrointestinal tract. Innate responses arc activated by direct contact with bacteria or their metabolic products, leading to production of antimicrobial substances that fight infection and secretion of chemokines and cytokines that enhance acquired, antigen-specific immune responses. Transcytosis of IgA antibodies across mucosal epithelia is mediated by the polymeric immunoglobulin receptor (plgR). Because of its role in neutralizing pathogens and potentially pro-inflammatory byproducts such as LPS, plgR can be viewed as an anti-inflammatory gene product of lEe. We recently discovered that plgR expression is up-regulated by exposure of a human IEC line to Escherichia coli or purified E. coli lipopolysaccharide (LPS), a ligand for Toll-like receptor ..t (TLR4). We found that LPS up-regulated plgR expression without inducing a strong pro-inflammatory rcponse, suggesting that TLR4 signaling pathways may differ for pro- and anti-inflammatory genes. We further demonstrated that oral administration of the antibiotic metronidazole, a therapeutic used to reduce numbers of colonic bacteria in IBD patients, caused a significant decrease in pIgR expression in wild-type but not TLR4-deficient mice. Thus. appropriate responses of IEC to colonic bacteria may promote intestinal homeostasis by maintaining a balance between pro- and anti-inflammatory gene expression. The goal of the proposed research is to measure changes in gene expression and rates of IgA transcytosis in vivo and in vitro in response to TLR4 signaling.
Effective start/end date1/2/066/30/08


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