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 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-1beta 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-kappaBalpha (I-kappaBalpha) and subsequent cytoplasmic mobilization, DNA-binding and the transactivating potential of nuclear factor-kappaB (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.
Burgermeister
E
E
Department of Molecular Pharmacology, Roche Diagnostics, Nonnenwald. 2, D-82372, Penzberg, Germany.
Pessara
U
U
Tibes
U
U
Küster
A
A
Heinrich
P C
PC
Scheuer
W V
WV
D016718:Arachidonic Acid / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007975:Leukotriene B4 / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010972:Platelet Activating Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D007975:Leukotriene B4; D016718:Arachidonic Acid; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A