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P2Y6 RECEPTOR STIMULATES CXCL8 SECRETION. IS THERE A LINK WITH INTESTINAL INFLAMMATION?
D Grbic, E Degagné, C Langlois, A-A Dupuis, FP Gendron
CHIR Team on the Digestive Epithelium, Department of anatomy and cell biology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke
BACKGROUND & AIMS: Extracellular nucleotides can activate P2Y nucleotide receptors and participate to the inflammatory response. However their involvements in IBDs are not known. We thus investigated the role of extracellular nucleotides and their associated P2Y receptors in the secretion of cytokines by epithelial cells.
METHODS: 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 DSS-treated mice. The effect of the P2Y6 activation by UDP on cytokine expression and release by epithelial cells was determined using combination of western blots, luciferase assays, PCR, cytokine antibody arrays and ELISA tests.
RESULTS: Inflammation up-regulates P2Y2 as well as P2Y6 receptor expression in the colonic mucosa of DSS-treated mice, and in tissue samples of patients suffering from Crohn’s disease and ulcerative colitis. In vitro, we have confirmed the increased expression of P2Y6 by challenging IEC-6 and Caco-2/15 cells with TNF-alpha and INF-gamma. Stimulation of epithelial cells by UDP results in an increased expression and release of CXCL8 by an ERK 1/2-dependent mechanism. Finally, the increase in CXCL8 expression was associated with its transcriptional activation by the P2Y6 receptor.
CONCLUSIONS: This work is the first demonstration that P2Y receptors (P2Y6) of the intestinal epithelial cells can contribute to the immune responses of the intestinal epithelium. These results clearly demonstrate the emergence of extracellular nucleotide signalling in the orchestration of intestinal inflammation.
This research was supported by the CCFC and a FRSQ scholarship to FP. Gendron.