Submitted on November 30, 2006
Revised on December 14, 2006
Accepted on December 18, 2006
Biosynthesis of eicosanoids and transcellular metabolism of leukotrienes in murine bone marrow cells
Miguel A. Gijón, Simona Zarini, and Robert C. Murphy
Pharmacology, University of Colorado Health Sciences Center, Aurora, CO 80045-0511
Corresponding Author: robert.murphy{at}uchsc.edu
Leukotriene B4 (LTB4) biosynthesis by polymorphonuclear leukocytes (PMNs) is an important factor of inflammatory responses. PMNs also release leukotriene A4 (LTA4), an unstable intermediate that can be taken up by neighboring cells and metabolized into leukotriene C4 (LTC4). Most studies on 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 that observed with human blood neutrophil preparations. Human megakaryoblast-like MEG-01 cells synthesized TXB2 and PGE2 in response to A23187, but produced no 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.
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