A downstream role for protein kinase Cα in the cytosolic phospholipase A 2-dependent protective signalling mediated by peroxynitrite in U937 cells

Abstract

Exposure to an otherwise non-toxic concentration of peroxynitrite (ONOO −) promotes toxicity in U937 cells supplemented with pharmacological inhibitors of protein kinase C (PKC). This effect is not associated with enhanced formation of H 2O 2 and is in fact causally linked to inhibition of the cytoprotective signalling driven by endogenous arachidonic acid (AA). The outcome of various approaches using PKC or phospholipase A 2 inhibitors, cytosolic phospholipase A 2 or PKCα antisense-oligonucleotide-transfected cells and supplementation with exogenous AA or tetradecanoylphorbol acetate, as well as PKC down-regulated cells, indicated that ONOO − promotes AA-dependent cytosol to membrane translocation of PKCα, an event critical for the cytoprotective signalling under investigation. Evidence for a similar mechanism regulating survival of human monocytes exposed to ONOO − is also presented. These results, along with our previous work on this topic, contribute to the definition of the mechanism whereby monocytes survive to ONOO − in inflamed tissues.