Abstract
The role of Group IVA cytosolic phospholipase A2 (cPLA2α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA2α+/+ than cPLA2α-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2α+/+ than cPLA2α-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2α+/+ and cPLA2α-/- macrophages (3 h) was compared by microarray. cPLA2α+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2α-/- macrophages (≥2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnfα, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifnγ, several IFNγ-inducible GTPases). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2α+/+ macrophages. Representative genes expressed lower in cPLA2α+/+ macrophages (Tnfα, Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.
Highlights
The oxygenated metabolites of arachidonic acid comprise a large family of bioactive lipids that have diverse roles in regulating homeostatic processes and in modulating inflammation and immune responses [1]
Our results demonstrate that C. albicans-stimulated cPLA2α activation and the early production of prostanoids promotes an autocrine pathway in RPM that affects the expression of genes involved in host defense and to dampen inflammation
The major arachidonic acid metabolites produced by RPM in response to C. albicans and zymosan are PGI2, PGE2, and LTC4, and their production is dependent on cPLA2α activation to provide arachidonic acid substrate [12,13,14]
Summary
The oxygenated metabolites of arachidonic acid comprise a large family of bioactive lipids that have diverse roles in regulating homeostatic processes and in modulating inflammation and immune responses [1]. The production of eicosanoids is initiated by the release of arachidonic acid that is metabolized through the 5-lipoxygenase pathway to leukotrienes and by cyclooxygenases (COX) to prostanoids and thromboxane. Eicosanoids are secreted and act locally in an autocrine or paracrine fashion through interaction with specific G-protein coupled receptors (GPCR) to exert their biological effects [2,3,4]. Leukotrienes are pro-inflammatory mediators but prostaglandins (PG) have pro- and antiinflammatory effects depending on the cell type-specific GPCRdependent signal transduction pathways that are triggered [1]. Macrophages are an important source of eicosanoids that are produced rapidly in response to stimulation by bacterial and fungal pathogens [5,6,7,8]. Resident tissue macrophages are a first line of defense against invading microorganisms that are recognized by pattern recognition receptors that engage microbial surface structures.
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