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Prostaglandin E 2 couples through EP 4 prostanoid receptors to induce IL‐8 production in human colonic epithelial cell lines
Author(s) -
Dey I,
Giembycz MA,
Chadee K
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00056.x
Subject(s) - receptor , prostaglandin e2 receptor , prostanoid , agonist , prostaglandin e , prostaglandin d2 , endocrinology , medicine , receptor antagonist , biology , prostaglandin , protease activated receptor 2 , microbiology and biotechnology , chemistry , enzyme linked receptor , antagonist
Mandarin translation of abstract Background and purpose: Prostaglandin (PG) E 2 and interleukin (IL)‐8 are simultaneously increased during the inflammation that characterizes numerous pathologies such as inflammatory bowel disease. IL‐8 is a potent neutrophil chemo‐attractant and activator, and can initiate and/or exacerbate tissue injury. PGE 2 signals principally through prostanoid receptors of the EP 2 and/or EP 4 subtypes to promote cAMP‐dependent cellular functions. The aim of this study was to identify the role of the EP 2 and EP 4 receptor subtype(s) on two human colonic epithelial cell lines (Caco‐2 and T84), in regulating PGE 2 ‐induced IL‐8 production. Experimental approach: To identify the causative receptor, we knocked‐down and over‐expressed EP 2 and EP 4 receptor subtypes in colonic epithelial cells and studied the effect of several selective EP 2 /EP 4 receptor agonists and antagonists. The inductions of IL‐8 and EP receptor mRNA and protein expression were determined by real‐time PCR and western blot analysis. The affinity of PGE 2 and Bmax values for the EP 2 and EP 4 receptor on colonic epithelial cells were determined by radioligand‐binding assays with [ 3 H]PGE 2 . Key results: PGE 2 had the highest affinity for the EP 4 receptor subtype and promoted a robust stimulation of cAMP‐dependent IL‐8 synthesis. This effect was mimicked by a selective EP 4 receptor agonist, ONO‐AE1‐329, and abolished by silencing the EP 4 receptor gene by using siRNA techniques, a selective EP 4 receptor antagonist (ONO‐AE3‐208) and a selective inhibitor (Rp‐cAMP) of cAMP‐dependent protein kinase. Conclusions and implications: These findings suggest that initiation and progression of colonic inflammation induced by IL‐8 could be mediated, at least in part, by PGE 2 acting via the EP 4 receptor subtype. British Journal of Pharmacology (2009) 10.1111/j.1476‐5381.2008.00056.x Mandarin translation of abstract