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Published online before print November 7, 2005

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(Journal of Leukocyte Biology. 2006;79:223-234.)
© 2006 by Society for Leukocyte Biology

Impaired NADPH oxidase activity in Rac2-deficient murine neutrophils does not result from defective translocation of p47^phox and p67^phox and can be rescued by exogenous arachidonic acid

Chaekyun Kim^*, and Mary C. Dinauer^*,1

^* Herman B. Wells Center for Pediatric Research, Department of Pediatrics (Hematology/Oncology), Microbiology/Immunology, and Medical and Molecular Genetics, James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis; and
Inha University College of Medicine, Incheon, Korea

¹ Correspondence: Cancer Research Institute, Indiana University School of Medicine, 1044 West Walnut Street, R4 402C, Indianapolis, IN 46202. E-mail: mdinauer{at}iupui.edu

Rac2 is a hematopoietic-specific Rho-GTPase that plays a stimulus-specific role in regulating reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and other functional responses in neutrophils. In this study, rac2-/- neutrophils were shown to have significantly decreased NADPH oxidase activity and actin remodeling in response to exogenous arachidonic acid (AA), as previously observed for phorbol 12-myristate 13-acetate (PMA) or formyl-Met-Leu-Phe (fMLP) as agonists. PMA-, fMLP-, or AA-induced translocation of p47^phox and p67^phox to the plasma membrane was not impaired in rac2-/- neutrophils. Combined stimulation of rac2-/- neutrophils with exogenous AA and PMA had a synergistic effect on NADPH oxidase activity, and superoxide production increased to a level that was at least as high as wild-type cells and had no effect on fMLP-elicited enzyme activity. Membrane translocation of p47^phox and p67^phox as well as Rac1 activation was not increased further by combined PMA and AA stimulation. Inhibitor studies were consistent with important roles for phorbol ester-activated protein kinase C (PKC) isoforms and an atypical isoform, PKC, in superoxide production by wild-type and rac2-/- neutrophils stimulated with AA and PMA. In addition, PMA-stimulated release of AA and cytoplasmic phospholipase A₂ expression in rac2-/- neutrophils were similar to wild-type, suggesting that deficient AA production by PMA-stimulated rac2-/- neutrophils does not explain the effect of exogenous AA on oxidase activity. Although not required for translocation of p47^phox and p67^phox, Rac2 is necessary for optimal activity of the assembled oxidase complex, an effect that can be replaced by exogenous AA, which may act directly or via an exogenous AA-induced mediator.

Key Words: cPLA₂ • PKC • superoxide anion • Rho-GTPase

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