Co-operative signalling through DP 1 and DP 2 prostanoid receptors is required to enhance leukotriene C 4 synthesis induced by prostaglandin D 2 in eosinophils

Abstract

BACKGROUND AND PURPOSE: Prostaglandin (PG) D 2 has emerged as a key mediator of allergic inflammatory pathologies and, particularly, PGD 2 induces leukotriene (LT) C 4 secretion from eosinophils. Here, we have characterized how PGD 2 signals to induce LTC 4 synthesis in eosinophils. EXPERIMENTAL APPROACH Antagonists and agonists of DP 1 and DP 2 prostanoid receptors were used in a model of PGD 2-induced eosinophilic inflammation in vivo and with PGD 2-stimulated human eosinophils in vitro, to identify PGD 2 receptor(s) mediating LTC 4 secretion. The signalling pathways involved were also investigated. KEY RESULTS In vivo and in vitro assays with receptor antagonists showed that PGD 2-triggered cysteinyl-LT (cysLT) secretion depends on the activation of both DP 1 and DP 2 receptors. DP 1 and DP 2 receptor agonists elicited cysLTs production only after simultaneous activation of both receptors. In eosinophils, LTC 4 synthesis, but not LTC 4 transport/export, was activated by PGD 2 receptor stimulation, and lipid bodies (lipid droplets) were the intracellular compartments of DP 1/DP 2 receptor-driven LTC 4 synthesis. Although not sufficient to trigger LTC 4 synthesis by itself, DP 1 receptor activation, signalling through protein kinase A, did activate the biogenesis of eosinophil lipid bodies, a process crucial for PGD 2-induced LTC 4 synthesis. Similarly, concurrent DP 2 receptor activation used Pertussis toxin-sensitive and calcium-dependent signalling pathways to achieve effective PGD 2-induced LTC 4 synthesis. CONCLUSIONS AND IMPLICATIONS Based on pivotal roles of cysLTs in allergic inflammatory pathogenesis and the collaborative interaction between PGD 2 receptors described here, our data suggest that both DP 1 and DP 2 receptor antagonists might be attractive candidates for anti-allergic therapies. © 2011 The British Pharmacological Society.