Inhibition of cytosolic phospholipase A(2) attenuates activation of mitogen-activated protein kinases in human monocytic cells

Eicosanoids and platelet-activating factor generated upon activation of cyt osolic phospholipase A(2) enhance activity of transcription factors and syn thesis of proinflammatory cytokines. Here, we show that selective inhibitor s and antisense oligonucleotides against this enzyme suppressed expression of the interleukin-1 beta gene at the level of transcription and promoter a ctivation in human monocytic cell lines. This inhibitory effect was due to failure of activation of mitogen-activated protein kinases (MAPK) through p hosphorylation by upstream mitogen-activated protein kinase kinases (MKK). Consequently, phosphorylation and degradation of inhibitor-kappa B alpha (I -kappa B alpha) and subsequent cytoplasmic mobilization, DNA-binding and th e transactivating potential of nuclear factor-kappa B (NF-kB), nuclear fact or-interleukin-6 (NF-IL6), activation protein-1 (AP-1) and signal-transduce r-and-activator-of-transcription-1 (STAT-1) were impaired. It is concluded, that lipid mediators promote activation of MAPKs, which in turn lead to ph osphorylation and liberation of active transcription factors. Since inhibit ion of cytosolic phospholipase A(2) ameliorates inflammation in vivo, this potency may reside in interference with the MAPK pathway. (C) 2000 Elsevier Science B.V. All rights reserved.