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Group V Phospholipase A2 Induces Leukotriene Biosynthesis in Human Neutrophils through the Activation of Group IVA Phospholipase A2

Kim, Young Jun and Kim, Kwang Pyo and Han, Sang Kyou and Munoz, Nilda M. and Zhu, Xiangdong and Sano, Hiroyuki and Leff, Alan R. and Cho, Wonhwa (2002) Group V Phospholipase A2 Induces Leukotriene Biosynthesis in Human Neutrophils through the Activation of Group IVA Phospholipase A2. Journal of Biological Chemistry, 277 (39). pp. 36479-36488. ISSN 0021-9258.

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We reported previously that exogenously added human group V phospholipase A2 (hVPLA2) could elicit leukotriene B4 (LTB4) biosynthesis in human neutrophils (Han, S. K., Kim, K. P., Koduri, R., Bittova, L., Munoz, N. M., Leff, A. R., Wilton, D. C., Gelb, M. H., and Cho, W. (1999) J. Biol. Chem. 274, 11881-11888). To determine the mechanism of the hVPLA2-induced LTB4 biosynthesis in neutrophils, we thoroughly examined the effects of hVPLA2 and their lipid products on the activity of group IVA cytosolic PLA2 (cPLA2) and LTB4 biosynthesis under different conditions. As low as 1 nM exogenous hVPLA2 was able to induce the release of arachidonic acid (AA) and LTB4. Typically, AA and LTB4 were released in two phases, which were synchronized with a rise in intracellular calcium concentration ([Ca2+]i) near the perinuclear region and cPLA2 phosphorylation. A cellular PLA2 assay showed that hVPLA2 acted primarily on the outer plasma membrane, liberating fatty acids and lysophosphatidylcholine (lyso-PC), whereas cPLA2 acted on the perinuclear membrane. Lyso-PC and polyunsaturated fatty acids including AA activated cPLA2 and 5-lipoxygenase by increasing [Ca2+]i and inducing cPLA2 phosphorylation, which then led to LTB4 biosynthesis. The delayed phase was triggered by the binding of secreted LTB4 to the cell surface LTB4 receptor, which resulted in a rise in [Ca2+]i and cPLA2 phosphorylation through the activation of mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2. These results indicate that a main role of exogenous hVPLA2 in neutrophil activation and LTB4 biosynthesis is to activate cPLA2 and 5-lipoxygenase primarily by liberating from the outer plasma membrane lyso-PC that induces [Ca2+]i increase and cPLA2 phosphorylation and that hVPLA2-induced LTB4 production is augmented by the positive feedback activation of cPLA2 by LTB4.

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Additional Information:© 2002 The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, May 31, 2002, and in revised form, July 16, 2002. Published, JBC Papers in Press, July 17, 2002, DOI 10.1074/jbc.M205399200. This work was supported by National Institutes of Health Grants GM52598 (to W. C.) and HL46368 and HL56399 (to A. R. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Issue or Number:39
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ID Code:5598
Deposited By: Archive Administrator
Deposited On:25 Oct 2006
Last Modified:02 Oct 2019 23:24

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