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Canadian Institutes of Health Research Team on the Digestive Epithelium, Département d’Anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada
Epithelial cells participate in the immune response of the intestinal mucosa. Extracellular nucleotides have been recognized as inflammatory molecules. We investigated the role of extracellular nucleotides and their associated P2Y receptors in the secretion of cytokines by epithelial cells. The effect of intestinal inflammation on P2Y6 receptor expression was determined by PCR in the mouse, rat, and human. Localization of the P2Y6 receptor was determined by immunofluorescence microscopy in the colon of normal and dextran sulfate sodium-treated mice. The effect of P2Y6 activation by UDP on cytokine expression and release by epithelial cells was determined using a combination of Western blots, luciferase assays, RT-PCR, cytokine Ab arrays, and ELISA. Inflammation up-regulates P2Y2 as well as P2Y6 receptor expression in the mucosa of the colon of colitic mice. In vitro, we demonstrated that UDP could be released by Caco-2/15 cells. We have confirmed the increased expression of P2Y6 by challenging intestinal epithelial cell-6 and Caco-2/15 cells with TNF-
and IFN-
and showing that stimulation of epithelial cells by UDP results in an increased expression and release of CXCL8 by an ERK1/2-dependent mechanism. The increase in CXCL8 expression was associated with a transcriptional activation by the P2Y6 receptor. This study is the first report demonstrating the implication of P2Y receptors in the inflammatory response of intestinal epithelial cells. We show for the first time that P2Y6, as well as P2Y2, expression is increased by the stress associated with intestinal inflammation. These results demonstrate the emergence of extracellular nucleotide signaling in the orchestration of intestinal inflammation.
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1 This work was supported by the Crohn’s and Colitis Foundation of Canada Grant in Aid of Research and an establishment grant from the Fonds de la Recherche en Santé du Québec. F.-P.G. is a scholar from the Fonds de la Recherche en Santé du Québec and a member of the Fonds de la Recherche en Santé du Québec-funded Centre de Recherche Clinique Étienne Lebel.
2 Address correspondence and reprint requests to Dr. Fernand-Pierre Gendron, Département d’Anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, QC, Canada, J1H 5N4. E-mail address: Fernand-P.Gendron{at}USherbrooke.ca
3 Abbreviations used in this paper: IEC, intestinal epithelial cell; AUC, area under the curve; DSS, dextran sulfate sodium; E-NTPDase, ecto-nucleoside triphosphate diphosphohydrolase; IBD, inflammatory bowel disease; MRS2578, N,N''-1,4-butanediyl bis(N'-[3-isothiocynatophenyl]) thiourea; PPADS, pyridoxal-5-phosphate-6-azophenyl-2'4'-disulfonic acid; RT, room temperature.
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