Activation of nuclear factor-κB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A2

In monocytes, lipopolysaccharide induces synthesis and activity of the 85-kDa cytosolic phospholipase A(2). This enzyme releases arachidonic acid and lyso-phospholipids from membranes which are metabolized to eicosanoids and platelet-activating-factor. These lipid mediators increase activity of transcription factors and expression of cytokine genes indicating a function for cytosolic phospholipase A(2) in signal transduction and inflammation. We have shown previously that trifluoromethylketone inhibitors of cytosolic phospholipase A(2) suppressed interleukin-1 beta protein and steady-state mRNA levels in human lipopolysaccharide-stimulated peripheral blood mononuclear leukocytes. In this study, the subcellular mechanisms were analyzed by which trifluoromethylketones interfere with gene expression. We found that they reduced the initial interleukin-1 beta mRNA transcription rate through prevention of degradation of inhibitor-kappa B alpha. Consequently, cytosolic activation, nuclear translocation and DNA-binding of nuclear factor-kappa B were decreased. Trifluoromethylketones ameliorate chronic inflammation in vivo. Thus, this therapeutic potency may reside in retention of inactive nuclear factor-kappa B in the cytosol thereby abrogating interleukin-1 beta gene transcription. (C) 1999 Elsevier Science B.V. All rights reserved.