Cytosolic Phospholipase A(2)α and Eicosanoids Regulate Expression of Genes in Macrophages Involved in Host Defense and Inflammation

The role of Group IVA cytosolic phospholipase A(2) (cPLA(2)α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA(2)α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E(2) and leukotriene C(4) were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA(2)α(+/+) than cPLA(2)α(-/-) macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA(2)α(+/+) than cPLA(2)α(-/-) macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA(2)α(+/+) and cPLA(2)α(-/-) macrophages (3 h) was compared by microarray. cPLA(2)α(+/+) macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA(2)α(-/-) 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 cPLA(2)α(+/+) macrophages. Representative genes expressed lower in cPLA(2)α(+/+) 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 cPLA(2)α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.