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J. Biol. Chem., Vol. 282, Issue 28, 20151-20163, July 13, 2007

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Activated Platelets and Monocytes Generate Four Hydroxyphosphatidylethanolamines via Lipoxygenase^*

Benjamin H. Maskrey, Alexandra Bermúdez-Fajardo, Alwena H. Morgan, Esther Stewart-Jones, Vincent Dioszeghy, Graham W. Taylor, Paul R. S. Baker^¶, Barbara Coles, Marcus J. Coffey, Hartmut Kühn^||, and Valerie B. O'Donnell¹

From the Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom, Centre for Amyloidosis and Acute Phase Proteins, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, ^¶Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and ^||Institute of Biochemistry, Humboldt University, D10117 Berlin, Germany

12/15-Lipoxygenase (LOX) mediates immune-regulatory activities not accounted for by its known free acid eicosanoids, suggesting that additional lipids may be generated by activated cells. To characterize novel LOX-derived lipids, a lipidomic approach was utilized. Ionophore-activated interleukin-4-treated human peripheral monocytes generated up to 10-fold more esterified 15-hydroxyeicosatetraenoic acid (15-HETE) than free in a phosphatidylinositol 3-kinase- and protein kinase C-sensitive manner. Precursor scanning electrospray ionization/tandem spectroscopy for m/z 319 (HETE, [M-H]^–) showed 4 ions at m/z 738, 764, 766, and 782 that were identified using tandem spectroscopy and MS3 as specific diacyl and plasmalogen 15-HETE phosphatidylethanolamines. Using H ¹⁸₂O water, the compounds were shown to form by direct oxidation of endogenous phosphatidylethanolamine (PE) by 15-LOX, with PE being the preferred phospholipid pool containing 15-HETE. Similarly, human platelets generated 4 analogous PE lipids that contained 12-HETE and increased significantly in response to ionophore, collagen, or convulxin. These products were retained in the cells, in contrast to free acids, which are primarily secreted. Precursor scanning of platelet extracts for the major platelet-derived prostanoid, thromboxane B2 (m/z 369.2), did not reveal PE esters, indicating that this modification is restricted to the LOX pathway. In summary, we show formation of PE-esterified HETEs in immune cells that may contribute to LOX signaling in inflammation.

Received for publication, December 22, 2006 , and in revised form, May 21, 2007.

^* This work was supported by the Wellcome Trust, British Heart Foundation, and Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-29-2074-8447; E-mail: o-donnellvb{at}cardiff.ac.uk.

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