Docosahexaenoic acid-derived oxidized lipid metabolites modulate the inflammatory response of lipolysaccharide-stimulated macrophages

Docosahexaenoic acid (DHA) supplementation has demonstrated beneficial effects in a number of inflammatory diseases. Increasingly, important contributions to its favorable effects are attributed downstream metabolites called docosanoids. Herein, we investigated the role of DHA-derived oxidized lipid metabolites on inflammatory mediator expression by RAW 264.7 murine macrophages. Specifically, macrophage incorporation of DHA, and the resultant biosynthesis of selected pro-resolving docosanoids was quantified. Docosanoid effects on the expression of selected pro-inflammatory cytokines in LPS-stimulated cultures was determined. Macrophages incorporated DHA in significant amounts. In the presence of DHA macrophages produced statistically significant amounts of several putative pro-resolving docosanoids compared to untreated controls. Among them, resolvins D1 and D2 and maresin 1 abrogated COX-2 and IL-1β gene expression in LPS-stimulated macrophages. In addition to these mediators, protectin DX inhibited LPS-stimulated macrophage expression of IL-6. Our results demonstrate that macrophages incorporate DHA in quantities sufficient for the biosynthesis of biologically-relevant concentrations of a number of pro-resolving docosanoids, certain of which modulate the inflammatory response of macrophages under conditions mimicking acute inflammation. These data provide further information on the mechanism(s) by which DHA exerts salutary effects on the inflammatory response of macrophages.