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B and Stimulates Cyclooxygenase-2 Expression and PGE2 Released by Intestinal Epithelial Cells1
* 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;
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada; and
Department of Biochemistry, University of Missouri, Columbia, MO 65211
Inflammatory stresses associated with inflammatory bowel diseases up-regulate P2Y2 mRNA receptor expression in the human colon adenocarcinoma cell line Caco-2, the noncancerous IEC-6 cells and in colonic tissues of patient suffering from Crohn’s disease and ulcerative colitis. However, the transcriptional events regulating P2Y2 receptor (P2Y2R) expression are not known. We have identified a putative transcription start site in the P2Y2R gene and demonstrated acetylation of Lys14 on histone H3 and Lys8 on histone H4, thus suggesting that the chromatin associated with the P2Y2 promoter is accessible to transcription factors. We also showed that the transcription factor NF-
B p65 regulates P2Y2R transcription under both proinflammatory and basal conditions. A NF-B-responsive element was identified at –181 to –172 bp in the promoter region of P2Y2. Hence, activation of P2Y2R by ATP and UTP stimulated cyclooxygenase-2 expression and PGE2 secretion by intestinal epithelial cells. These findings demonstrate that P2Y2R expression is regulated during intestinal inflammation through an NF-B p65-dependent mechanism and could contribute not only to inflammatory bowel disease but also to other inflammatory diseases by regulating PG release.
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1 This research was supported by the Crohn’s and Colitis Foundation of Canada Grant in Aid of Research, the Canadian Institutes of Health Research (CIHR, NMD-94729), and an establishment grant from the Fonds de la Recherche en Santé du Québec (FRSQ) (to F.P.G.); by grants from the CIHR (IMH-67520 and MOP-68957) and The Arthritis Society (to J.S.); and by National Institutes of Health Grants AG18357, DE07389, and DE17591 (to G.A.W.). F.P.G. is a scholar from the FRSQ and a member of the FRSQ-funded Centre de Recherche Clinique Étienne-Le Bel. D.M.G. is a recipient of a scholarship from the Natural Sciences and Engineering Research Council of Canada. J.S. was a recipient of a new investigator award from the CIHR, and E.G.L. received a scholarship from the FRSQ.
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 12e Avenue Nord, Sherbrooke, QC, Canada, J1H 5N4. E-mail address: Fernand-P.Gendron{at}USherbrooke.ca
3 Abbreviations used in this paper: IEC, intestinal epithelial cell; COX-2, cyclooxygenase-2; DSS, dextran sulfate sodium; HCAEC, human coronary artery endothelial cells; IBD, inflammatory bowel diseases; NBM, NF-B-binding motif; TSS, transcription starting site; ChIP, chromatin immunoprecipitation; RLM, RNA ligase mediated.
4 The online version of this article contains supplemental material.
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