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Published online before print July 8, 2005

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(Journal of Leukocyte Biology. 2005;78:976-984.)
© 2005 by Society for Leukocyte Biology

Leukotriene B₄ mediates p47phox phosphorylation and membrane translocation in polyunsaturated fatty acid-stimulated neutrophils

Carlos H. C. Serezani^*,, David M. Aronoff^*,, Sonia Jancar and Marc Peters-Golden^*,1

Divisions of Infectious Diseases and
^* Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor; and
Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, Brazil

¹Correspondence: Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 6301 MSRB III, Box 0642, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail: petersm{at}umich.edu

Polyunsaturated fatty acids (PUFAs) and leukotriene B₄ (LTB₄) are involved in many inflammatory and physiological conditions. The role of arachidonic acid (AA) and linoleic acid (LA) in promoting the assembly of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits is well known, but the involvement of LTB₄ and other 5-lipoxygenase (5-LO) pathway metabolites of AA in hydrogen peroxide (H₂O₂) production by PUFA-stimulated polymorphonuclear leukocytes (PMNs) has not been investigated. We examined this question by determining H₂O₂ production as well as phosphorylation and membrane translocation of the p47phox subunit of NADPH oxidase. Elicited peritoneal PMNs from rats and from 5-LO-deficient or wild-type mice were pretreated with or without inhibitors of LT biosynthesis and antagonists of the receptors for LTB₄ and cysteinyl LTs for 20 min before stimulation with AA (at 5 and 20 µM) or LA (at 20 µM). PUFAs elicited H₂O₂ production in a dose-dependent manner, and pharmacologic or genetic inhibition of LT synthesis decreased H₂O₂ production by 40% when compared with untreated controls. LTB₄ was the moiety responsible for H₂O₂ production, as revealed by studies using receptor antagonists and its exogenous addition. LTB₄ itself also promoted p47phox phosphorylation and translocation. These results identify a heretofore unrecognized role for activation of 5-LO and subsequent production of LTB₄ in stimulation of PMN NADPH oxidase activation by PUFAs.

Key Words: PMN • PUFAs • lipid mediators • NADPH oxidase • BLT1

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