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Activation of Group IV Cytosolic Phospholipase A₂ in Human Eosinophils by Phosphoinositide 3-Kinase Through a Mitogen-Activated Protein Kinase-Independent Pathway ¹

Shigeharu Myou^*, Alan R. Leff^2,*,, Saori Myo^*, Evan Boetticher^*, Angelo Y. Meliton^*, Anissa T. Lambertino, Jie Liu^*, Chang Xu^*, Nilda M. Munoz^* and Xiangdong Zhu^*

^* Section of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, University of Chicago, Chicago, IL 60637

Activation of group IV cytosolic phospholipase A₂ (gIV-PLA₂) is the essential first step in the synthesis of inflammatory eicosanoids and in integrin-mediated adhesion of leukocytes. Prior investigations have demonstrated that phosphorylation of gIV-PLA₂ results from activation of at least two isoforms of mitogen-activated protein kinase (MAPK). We investigated the potential role of phosphoinositide 3-kinase (PI3K) in the activation of gIV-PLA₂ and the hydrolysis of membrane phosphatidylcholine in fMLP-stimulated human blood eosinophils. Transduction into eosinophils of p85, a dominant negative form of class IA PI3K adaptor subunit, fused to an HIV-TAT protein transduction domain (TAT-p85) concentration dependently inhibited fMLP-stimulated phosphorylation of protein kinase B, a downstream target of PI3K. FMLP caused increased arachidonic acid (AA) release and secretion of leukotriene C₄ (LTC₄). TAT-p85 and LY294002, a PI3K inhibitor, blocked the phosphorylation of gIV-PLA₂ at Ser⁵⁰⁵ caused by fMLP, thus inhibiting gIV-PLA₂ hydrolysis and production of AA and LTC₄ in eosinophils. FMLP also caused extracellular signal-related kinases 1 and 2 and p38 MAPK phosphorylation in eosinophils; however, neither phosphorylation of extracellular signal-related kinases 1 and 2 nor p38 was inhibited by TAT-p85 or LY294002. Inhibition of 1) p70 S6 kinase by rapamycin, 2) protein kinase B by Akt inhibitor, or 3) protein kinase C by Ro-31-8220, the potential downstream targets of PI3K for activation of gIV-PLA₂, had no effect on AA release or LTC₄ secretion caused by fMLP. We find that PI3K is required for gIV-PLA₂ activation and hydrolytic production of AA in activated eosinophils. Our data suggest that this essential PI3K independently activates gIV-PLA₂ through a pathway that does not involve MAPK.

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