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BACKGROUND AND PURPOSE: Prostaglandin (PG) D2 has emerged as a key mediator of allergic inflammatory pathologies and, particularly, PGD2 induces leukotriene (LT) C4 secretion from eosinophils. Here, we have characterized how PGD2 signals to induce LTC4 synthesis in eosinophils.

EXPERIMENTAL APPROACH: Antagonists and agonists of DP1 and DP2 prostanoid receptors were used in a model of PGD2-induced eosinophilic inflammation in vivo and with PGD2-stimulated human eosinophils in vitro, to identify PGD2 receptor(s) mediating LTC4 secretion. The signalling pathways involved were also investigated.

KEY RESULTS: In vivo and in vitro assays with receptor antagonists showed that PGD2-triggered cysteinyl-LT (cysLT) secretion depends on the activation of both DP1 and DP2 receptors. DP1 and DP2 receptor agonists elicited cysLTs production only after simultaneous activation of both receptors. In eosinophils, LTC4 synthesis, but not LTC4 transport/export, was activated by PGD2 receptor stimulation, and lipid bodies (lipid droplets) were the intracellular compartments of DP1/DP2 receptor-driven LTC4 synthesis. Although not sufficient to trigger LTC4 synthesis by itself, DP1 receptor activation, signalling through protein kinase A, did activate the biogenesis of eosinophil lipid bodies, a process crucial for PGD2-induced LTC4 synthesis. Similarly, concurrent DP2 receptor activation used Pertussis toxin-sensitive and calcium-dependent signalling pathways to achieve effective PGD2-induced LTC4 synthesis.

CONCLUSIONS AND IMPLICATIONS: Based on pivotal roles of cysLTs in allergic inflammatory pathogenesis and the collaborative interaction between PGD2 receptors described here, our data suggest that both DP1 and DP2 receptor antagonists might be attractive candidates for anti-allergic therapies.

LINKED ARTICLE: This article is commented on by Mackay and Stewart, pp. 1671-1673 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01236.x

Copyright (C) 2011 John Wiley & Sons, Inc.