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Originally published online as doi:10.1189/jlb.0107019 on August 30, 2007

Published online before print August 30, 2007
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(Journal of Leukocyte Biology. 2007;82:1585-1591.)
© 2007 by Society for Leukocyte Biology

NADPH oxidase deficiency results in reduced alveolar macrophage 5-lipoxygenase expression and decreased leukotriene synthesis

Michael J. Coffey1,2, Carlos H. Serezani1, Susan M. Phare, Nicolas Flamand and Marc Peters-Golden

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA

2Correspondence: Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 6301 MSRBIII, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0642, USA. E-mail: coffeym{at}umich.edu

Reactive oxygen intermediates (ROI) play an important role in cell signaling in addition to their role in microbial killing. We have shown previously that exogenous ROI regulate activity of the enzyme 5-lipoxygenase (5-LO) in alveolar macrophages (AM). Here, we examined the role of endogenous ROI, specifically generated by NADPH oxidase, in the regulation of leukotriene (LT) synthetic capacity in AM, which from NADPH oxidase knockout (KO) mice, was significantly less than that from wild-type (WT) AM. The decrease in LT synthesis could not be explained by reduced release of the substrate for 5-LO, arachidonic acid. However, the expression of 5-LO was reduced ~50% in AM from NADPH oxidase KO mice compared with WT mice. Reduced 5-LO expression could be reproduced by treating WT AM with ROI scavengers and with selective pharmacologic inhibitors of NADPH oxidase. Furthermore, conditioned media from WT AM augmented 5-LO metabolism in AM from NADPH oxidase KO mice. This decrease in 5-LO expression in NADPH oxidase KO cells was associated with decreased expression of the transcription factors, specificity protein-1 and early growth response-1, both of which are known to regulate 5-LO mRNA expression. These data reveal a previously unrecognized influence of endogenous ROI generated by NADPH oxidase on expression of the key LT biosynthetic protein, 5-LO. In view of the antimicrobial actions of LT, a reduction in LT synthetic capacity by AM from NADPH oxidase KO mice may contribute to the susceptibility of these animals to infection.

Key Words: eicosanoid • reactive oxygen intermediate