Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0406240 on August 2, 2006

Published online before print August 2, 2006
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(Journal of Leukocyte Biology. 2006;80:929-938.)
© 2006 by Society for Leukocyte Biology

5-Hydroxyeicosatetraenoic acid is a key intermediate of the arachidonate-dependent protective signaling in monocytes/macrophages exposed to peroxynitrite

Ilaria Tommasini, Andrea Guidarelli, Letizia Palomba, Liana Cerioni and Orazio Cantoni1

Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo," Urbino, Italy

1 Correspondence: Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo," Via S. Chiara, 27, Urbino (PU) 61029, Italy. E-mail: cantoni{at}uniurb.it

Endogenous generation of arachidonic acid via selective activation of cytosolic phospholipase A2 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 C{alpha} (PKC{alpha}) 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-XL). Here, we show that the effects on PKC{alpha} 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 PKC{alpha}, 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.

Key Words: reactive nitrogen species • 5-lipoxygenase • mitochondria • cell survival




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