Genomes and Genes
CHEMOKINE RECEPTOR EXPRESSION ON INTESTINAL EPITHELIUM
Principal Investigator: MICHAEL DWINELL
Affiliation: Medical College of Wisconsin
Abstract: Intestinal epithelial cells express an array of cytokine and chemokine receptors allowing these cells to be targets for immune mediators. Human intestinal epithelial cells regulate nutrient and elctrolyte transport, maintain barrier integrity, and can release proinflammatory cytokines and chemokines in response to inflammatory mediators or microbial infection, consistent with an integral role for these cells in initiating and regulating mucosal innate and acquired immunity. The overall hypothesis of this proposal is that the defined array of chemokine receptors constitutively expressed by human intestinal epithelial cells activates G-protein-coupled signaling pathways permitting these cells to be functional targets of chemokine signaling. Studies in Aim 1 will characterize the cellular localization, ligand binding, and receptor internalization of chemokine receptors expressed by human intestinal epithelial cells. Intestinal epithelial cells are polarized into apical and basolateral domains, typically reflected in apical surface proteins specialized for nutrient absorption and ion secretion and basolateral membrane proteins specialized for maintenance of the electrochemical gradient. These studies will use molecular and immunocytochemical techniques to define the apical and basolateral cellular localization, ligand binding characteristics, and receptor internalization/desensitization of chemokine receptors constitutively expressed by intestinal epithelial cells in vitro. Studies in Aim 2 will use a step-wise approach to define the G-protein linked intracellular signaling pathways activated by chemokine receptors expressed by human intestinal epithelial cells. Chemokine receptors are coupled to specific G-proteins and activate several intracellular signaling pathways in varying cell types. These studies will focus on defining the specific G-protein activated and the intracellular signaling pathways utilized by chemokine receptors constitutively expressed by intestinal epithelial cells. Together these studies will provide insights into the potential immune mediated regulation of epithelial cell functions, e.g. ion secretion, through the convergence of intracellular regulatory signaling pathways in chemokine receptor expressing intestinal epithelial cells. The expression and signaling of chemokine receptors by human intestinal epithelial cells indicates these cells may respond in an autocrine or paracrine manner to enteric chemokine receptor ligangs and is consistent with the notion that these cells have an essential role in the mucosal response to inflammation.
Funding Period: 2000-09-01 - 2004-08-31
more information: NIH RePORT
- CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrityJennifer M Smith
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
Am J Physiol Gastrointest Liver Physiol 288:G316-26. 2005....
- Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasisM K Wendt
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226 0509, USA
Oncogene 25:4986-97. 2006..These data constitute the unique observation that silencing CXCL12 within colonic carcinoma cells greatly enhances their metastatic potential...
- Flagellin-independent regulation of chemokine host defense in Campylobacter jejuni-infected intestinal epitheliumPriscilla A Johanesen
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Infect Immun 74:3437-47. 2006..Chemokine secretion occurs despite Campylobacter evasion of the flagellin pattern recognition receptor, suggesting that alternate host defense strategies limit disease pathogenesis...