Inhibition of cytosolic phospholipase A2 attenuates activation of mitogen-activated protein kinases in human monocytic cells

Abstract Eicosanoids and platelet-activating factor generated upon activation of cytosolic phospholipase A 2 enhance activity of transcription factors and synthesis of proinflammatory cytokines. Here, we show that selective inhibitors and antisense oligonucleotides against this enzyme suppressed expression of the interleukin-1β gene at the level of transcription and promoter activation in human monocytic cell lines. This inhibitory effect was due to failure of activation of mitogen-activated protein kinases (MAPK) through phosphorylation by upstream mitogen-activated protein kinase kinases (MKK). Consequently, phosphorylation and degradation of inhibitor-κBα (I-κBα) and subsequent cytoplasmic mobilization, DNA-binding and the transactivating potential of nuclear factor-κB (NF-kB), nuclear factor-interleukin-6 (NF-IL6), activation protein-1 (AP-1) and signal-transducer-and-activator-of-transcription-1 (STAT-1) were impaired. It is concluded, that lipid mediators promote activation of MAPKs, which in turn lead to phosphorylation and liberation of active transcription factors. Since inhibition of cytosolic phospholipase A 2 ameliorates inflammation in vivo, this potency may reside in interference with the MAPK pathway.