P2Y2 receptor transcription is increased by NF-kappa B and stimulates cyclooxygenase-2 expression and PGE2 released by intestinal epithelial cells.
Inflammatory stresses associated with inflammatory bowel diseases up-regulate P2Y(2) 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 P2Y(2) receptor (P2Y(2)R) expression are not known. We have identified a putative transcription start site in the P2Y(2)R gene and demonstrated acetylation of Lys(14) on histone H3 and Lys(8) on histone H4, thus suggesting that the chromatin associated with the P2Y(2) promoter is accessible to transcription factors. We also showed that the transcription factor NF-kappaB p65 regulates P2Y(2)R transcription under both proinflammatory and basal conditions. A NF-kappaB-responsive element was identified at -181 to -172 bp in the promoter region of P2Y(2). Hence, activation of P2Y(2)R by ATP and UTP stimulated cyclooxygenase-2 expression and PGE(2) secretion by intestinal epithelial cells. These findings demonstrate that P2Y(2)R expression is regulated during intestinal inflammation through an NF-kappaB p65-dependent mechanism and could contribute not only to inflammatory bowel disease but also to other inflammatory diseases by regulating PG release.
Degagné
Emilie
E
Canadian Institutes of Health Research Team on the Digestive Epithelium, Département d'Anatomie et de Biologie Cellulaire, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Grbic
Djordje M
DM
Dupuis
Andrée-Anne
AA
Lavoie
Elise G
EG
Langlois
Christine
C
Jain
Nishant
N
Weisman
Gary A
GA
Sévigny
Jean
J
Gendron
Fernand-Pierre
FP
D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D058473:Receptors, Purinergic P2Y2; D051996:Transcription Factor RelA / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*
D018836:Inflammation Mediators; C546385:P2RY2 protein, human; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D051996:Transcription Factor RelA; D051546:Cyclooxygenase 2; D015232:Dinoprostone