Cytosolic phospholipase A(2)? and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation.
The role of Group IVA cytosolic phospholipase A2 (cPLA2?) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2? 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 TNF? was lower in C. albicans-stimulated cPLA2?(+/+) than cPLA2?(-/-) macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2?(+/+) than cPLA2?(-/-) macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2?(+/+) and cPLA2?(-/-) macrophages (3 h) was compared by microarray. cPLA2?(+/+) macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2?(-/-) macrophages (?2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnf?, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifn?, several IFN?-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 cPLA2?(+/+) macrophages. Representative genes expressed lower in cPLA2?(+/+) macrophages (Tnf?, 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 cPLA2?, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.