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J. Biol. Chem., Vol. 278, Issue 40, 38813-38820, October 3, 2003

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Human Group V Phospholipase A₂ Induces Group IVA Phospholipase A₂-independent Cysteinyl Leukotriene Synthesis in Human Eosinophils^*

Nilda M. Muñoz , Young Jun Kim , Angelo Y. Meliton , Kwang Pyo Kim , Sang-Kyou Han , Evan Boetticher , Eileen O'Leary ¶, Shigeharu Myou , Xiangdong Zhu , Joseph V. Bonventre ¶, Alan R. Leff  || and Wonhwa Cho  **

From the Department of Medicine, The University of Chicago, Chicago, Illinois 60637, the Department of Chemistry, University of Illinois, Chicago, Illinois 60607, and the ^¶Department of Medicine, Harvard Medical School, Massachusetts General Hospital East, Charlestown, Massachusetts 02129

We previously reported that exogenously added human group V phospholipase A₂ (hVPLA₂) could elicit leukotriene B₄ biosynthesis in human neutrophils through the activation of group IVA phospholipase A₂ (cPLA₂) (Kim, Y. J., Kim, K. P., Han, S. K., Munoz, N. M., Zhu, X., Sano, H., Leff, A. R., and Cho, W. (2002) J. Biol. Chem. 277, 36479-36488). In this study, we determined the functional significance and mechanism of the exogenous hVPLA₂-induced arachidonic acid (AA) release and leukotriene C₄ (LTC₄) synthesis in isolated human peripheral blood eosinophils. As low a concentration as 10 nM exogenous hVPLA₂ was able to elicit the significant release of AA and LTC₄ from unstimulated eosinophils, which depended on its ability to act on phosphatidylcholine membranes. hVPLA₂ also augmented the release of AA and LTC₄ from eosinophils activated with formyl-Met-Leu-Phe + cytochalasin B. A cellular fluorescent PLA₂ assay showed that hVPLA₂ had a lipolytic action first on the outer plasma membrane and then on the perinuclear region. hVPLA₂ also caused the translocation of 5-lipoxygenase from the cytosol to the nuclear membrane and a 2-fold increase in 5-lipoxygenase activity. However, hVPLA₂ induced neither the increase in intracellular calcium concentration nor cPLA₂ phosphorylation; consequently, cPLA₂ activity was not affected by hVPLA₂. Pharmacological inhibition of cPLA₂ and the hVPLA₂-induced activation of eosinophils derived from the cPLA₂-deficient mouse corroborated that hVPLA₂ mediates the release of AA and leukotriene in a cPLA₂-independent manner. As such, this study represents a unique example in which a secretory phospholipase induces the eicosanoid formation in inflammatory cells, completely independent of cPLA₂ activation.

Received for publication, March 11, 2003 , and in revised form, June 5, 2003.

^* This work was supported by National Institutes of Health Grants GM52598 (to W. C.), HL-46368 (to A. R. L.), Specialized Center of Research Grant HL-56399 (to A. R. L.), and a Center of Excellence grant from GlaxoSmithKline, UK (to A. R. L.). 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.

^|| To whom correspondence may be addressed: Section of Pulmonary and Critical Care Medicine, Dept. of Medicine, MC6076, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-1859; Fax: 773-702-9181; E-mail: aleff{at}medicine.bsd.uchicago.edu.

^** To whom correspondence may be addressed: Dept. of Chemistry (M/C 111), University of Illinois at Chicago, 845 West Taylor St., Chicago, IL 60607-7061. Tel.: 312-996-4883; Fax: 312-996-2183; E-mail: wcho{at}uic.edu.

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