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Journal of Lipid Research, Vol. 48, 716-725, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Biosynthesis of eicosanoids and transcellular metabolism of leukotrienes in murine bone marrow cells

Miguel A. Gijón, Simona Zarini and Robert C. Murphy¹

Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045-6511

Published, JLR Papers in Press, December 18, 2006.

¹ To whom correspondence should be addressed. e-mail: robert.murphy{at}uchsc.edu

Leukotriene B₄ (LTB₄) biosynthesis by polymorphonuclear leukocytes (PMNs) is an important factor of inflammatory responses. PMNs also release LTA₄, an unstable intermediate that can be taken up by neighboring cells and metabolized into LTC₄. Most studies of LT synthesis have been carried out using human PMNs, but very little information is available about mouse PMNs. Mouse bone marrow PMNs were found to synthesize eicosanoids upon stimulation with A23187, fMLP, or zymosan. The major eicosanoids produced are LTB₄ and 5-hydroxyeicosatetraenoic acid, with some nonenzymatic products of LTA₄ hydrolysis. No cysteinyl leukotrienes were produced, in contrast to what was observed with human blood neutrophil preparations. Human megakaryoblast-like MEG-01 cells synthesized thromboxane B₂ and prostaglandin E₂ in response to A23187 but produced no 5-lipoxygenase (5-LO)-derived eicosanoids. When mouse bone marrow cells (mBMCs) and MEG-01 cells were stimulated during coincubation, LTC₄ and LTD₄ were produced. Mouse peritoneal macrophages from 5-LO-deficient mice were able to synthesize LTC₄ when incubated with mBMCs from wild-type mice, demonstrating transcellular exchange of LTA₄ from mBMCs into murine peritoneal macrophages. These data demonstrate that murine bone marrow PMNs are a valid model for the study of LT biosynthesis, which now offers the possibility to investigate specific biochemical pathways through the use of transgenic mice.

Supplementary key words murine neutrophils • leukotriene B₄ • leukotriene C₄ • MEG-01 cells • mass spectrometry

Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; cPLA₂, cytosolic phospholipase A₂; cys-LT, cysteinyl leukotriene; 5-HETE, 5-hydroxyeicosatetraenoic acid; LC-MS/MS, liquid chromatography-tandem mass spectrometry; 5-LO, 5-lipoxygenase; LT, leukotriene; mBMC, mouse bone marrow cell; PG, prostaglandin; PMN, polymorphonuclear leukocyte; TX, thromboxane

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