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ROLE OF EP RECEPTORS IN PGE₂ INDUCED IL-8 PRODUCTION IN INFLAMMATORY BOWEL DISEASES

I Dey, P Beck, K Chadee
Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta

Even though PGE₂ and IL-8 are simultaneously over expressed in inflammatory bowel diseases (IBD), it is unclear how both these proinflammatory mediators are regulated. As PGE₂ coupling through EP2/4 receptors stimulate cAMP-dependent IL-8 gene expression and protein production, we theorize that PGE₂ can regulate IL-8 and play an important role in the pathogenesis of IBD. IL-8 is a potent neutrophil chemoattractant and activator that can initiate or exacerbate tissue injury. Given that PGE₂ only signals through EP receptors to exert its cellular functions, we measured the levels of EP receptors in colonic tissues derived from IBD patients by real time PCR. In all IBD tissues tested, EP2 and EP4 receptors was over-expressed eight to 10-fold as compared with normal controls. To determine which EP receptor subtype(s) are involved in up-regulating IL-8, we inhibited or over expressed EP2, EP3 and EP4 receptors separately in stably transfected Caco2 cells in vitro. In cells overexpressing EP4 receptors, PGE₂ stimulated cAMP and IL-8 production by ~500% and ~1700%, respectively. Similar results were obtained with PGE1-OH, an EP2/4 receptor specific agonist, whereas, butaprost an EP2 receptor specific and sulprostone an EP1/3 receptor agonist had no effect. Surprisingly, in EP4 antisense cells PGE₂ up-regulated the expression of EP2 receptor mRNA and protein to compensate for PGE₂ signalling suggesting the presence of cross regulation among the receptors. PGE₂ coupling through the EP4 receptor only phosphorylated ERK MAP kinases; p38MAPK and JNK were not involved in this pathway. Taken together, this study reveals that EP2 and EP4 receptors are over expressed during IBD and that PGE₂ preferentially couples through the EP4 receptor to stimulate cAMP-dependent IL-8 production in colonic epithelial cells.
This work was partially supported by the Canadian Institutes of Health Research and the Canadian Association of Gastroenterology-Axcan Pharma-CIHR Research and Fellowship Award

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