EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa

Prostaglandin E2 (PGE2) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP1-4) to PGE2-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; Isc) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE2 and PGE1-alcohol increased Isc in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP4 receptor antagonist, GW627368X alone. In addition, the EP2 agonist, butaprost increased Isc in all three preparations and these responses were inhibited by the non-selective EP1,2,3 receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP1 and EP3 receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP3-preferring agonist, sulprostone reduced Isc, indicative of Giα-signalling. Taken together these results indicate that PGE2-induced ion secretion is mediated predominantly by Gs-coupled EP4 receptors and also by EP2 receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNFα) and interleukin 1beta (IL1β) increased Isc and these responses were also inhibited by the EP4 receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP4 receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE2 is implicated in the aetiology.