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5‐Hydroxyeicosatetraenoic acid is a key intermediate of the arachidonate‐dependent protective signaling in monocytes/macrophages exposed to peroxynitrite
Author(s) -
Tommasini Ilaria,
Guidarelli Andrea,
Palomba Letizia,
Cerioni Liana,
Cantoni Orazio
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0406240
Subject(s) - peroxynitrite , cytosol , protein kinase c , arachidonic acid , biology , microbiology and biotechnology , mitochondrion , lipid signaling , mitochondrial permeability transition pore , phospholipase a2 , hydroxyeicosatetraenoic acid , biochemistry , programmed cell death , enzyme , signal transduction , superoxide , apoptosis
Endogenous generation of arachidonic acid via selective activation of cytosolic phospholipase A 2 has been implicated in the mechanism of monocytes/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger was shown to prevent the otherwise rapid onset of a mitochondrial permeability‐transition (MPT)‐dependent necrosis by causing the mitochondrial translocation of protein kinase Cα (PKCα) and the ensuing cytosolic accumulation of the Bcl‐2‐antagonist of cell death (Bad), an event promoting the anti‐MPT function of Bcl‐2 (or Bcl‐X L ). Here, we show that the effects on PKCα are not mediated directly by arachidonate but rather, by downstream products of the enzyme 5‐lipoxygenase (5‐LO). Peroxynitrite elicited the nuclear membrane translocation of 5‐LO and enhanced its enzymatic activity via a mechanism sensitive to low concentrations of inhibitors of 5‐LO or the 5‐LO‐activating protein, as well as to genetic depletion of the latter enzyme. Inhibition of 5‐LO activity was invariably associated with the cytosolic localization of PKCα, the mitochondrial accumulation of Bad, and a rapid MPT‐dependent necrosis. All these events were prevented by nanomolar concentrations of the 5‐LO product 5‐hydroxyeicosatetraenoic acid.