Prostaglandin E2 couples through EP4 prostanoid receptors to induce IL-8 production in human colonic epithelial cell lines
Article first published online: 23 JAN 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 156, Issue 3, pages 475–485, February 2009
How to Cite
Dey, I., Giembycz, M. and Chadee, K. (2009), Prostaglandin E2 couples through EP4 prostanoid receptors to induce IL-8 production in human colonic epithelial cell lines. British Journal of Pharmacology, 156: 475–485. doi: 10.1111/j.1476-5381.2008.00056.x
- Issue published online: 17 FEB 2009
- Article first published online: 23 JAN 2009
- Received 23 June 2008; revised 1 September 2008; accepted 7 October 2008
- EP receptors;
- colonic epithelial cells
Mandarin translation of abstract
Background and purpose: Prostaglandin (PG) E2 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. PGE2 signals principally through prostanoid receptors of the EP2 and/or EP4 subtypes to promote cAMP-dependent cellular functions. The aim of this study was to identify the role of the EP2 and EP4 receptor subtype(s) on two human colonic epithelial cell lines (Caco-2 and T84), in regulating PGE2-induced IL-8 production.
Experimental approach: To identify the causative receptor, we knocked-down and over-expressed EP2 and EP4 receptor subtypes in colonic epithelial cells and studied the effect of several selective EP2/EP4 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 PGE2 and Bmax values for the EP2 and EP4 receptor on colonic epithelial cells were determined by radioligand-binding assays with [3H]PGE2.
Key results: PGE2 had the highest affinity for the EP4 receptor subtype and promoted a robust stimulation of cAMP-dependent IL-8 synthesis. This effect was mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and abolished by silencing the EP4 receptor gene by using siRNA techniques, a selective EP4 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 PGE2 acting via the EP4 receptor subtype.
British Journal of Pharmacology (2009) 10.1111/j.1476-5381.2008.00056.x