PGE2 and the innate immune response

Abstract

Eicosanoids support local inflammation and exhibit immunomodulatory properties. Current views have focused on prostaglandin E2 (PGE2), because it is the most abundant and lasting eisosanoid in the inflammatory milieu due to the robust production elicited after challenge with pathogen-associated molecular patterns by the constitutive and the inducible COX isoforms. The different functions and cell distribution of E prostanoid (EP) receptors explain the difficulty so far encountered to delineate the actual role of PGE2 in the immune response. It is widely accepted that by acting in an autocrine/paracrine manner PGE2 induces a regulatory phenotype including the expression of IL-10, the inhibition of the release of IL-12 p70, and distinct effects on IL-23 production due to differential effects on the expression of the p40 and p19 (encoded by the gene il23) chains of this cytokine. Given that PGE2 may be released concomitantly with other lipid mediators, the definite assignment of a role for each mediator is not an easy task. Our studies on the regulation of the gene il23a have disclosed the cooperation of leukotriene B4, cysteinyl-leukotrienes, and the phospholipid mediator platelet-activating factor in the response to fungal patterns. These mediators, by acting concomitantly on their cognate G-protein coupled receptors, activate phospholipase Cß and enhance the Ca2+- and kinase-dependent routes initiated by fungal patterns involving Syk kinase and phospholipase Cλ. The autocrine production of these mediators has a robust effect on the activation of transcription factors such as CREB and ATF2 that cooperate with NF-κB to establish the cytokine signature.