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Role of Mitogen-Activated Protein Kinase-Mediated Cytosolic Phospholipase A₂ Activation in Arachidonic Acid Metabolism in Human Eosinophils¹

Xiangdong Zhu^*, Hiroyuki Sano^*, Kwang Pyo Kim, Akiko Sano^*, Evan Boetticher^*, Nilda M. Muñoz^*, Wonhwa Cho and Alan R. Leff^2,*

^* Section of Pulmonary and Critical Care Medicine, Department of Medicine and Department of Pharmacological and Physiological Sciences, Pediatrics, Anesthesia, and Critical Care, and Committees on Clinical Pharmacology and Cell Physiology, Division of Biological Sciences, University of Chicago, Chicago, IL 60637; and Department of Chemistry, University of Illinois, Chicago, IL 60607

The objective of this investigation was to determine the role of secretory and cytosolic isoforms of phospholipase A₂ (PLA₂) in the induction of arachidonic acid (AA) and leukotriene synthesis in human eosinophils and the mechanism of PLA₂ activation by mitogen-activated protein kinase (MAPK) isoforms in this process. Pharmacological activation of eosinophils with fMLP caused increased AA release in a concentration (EC₅₀ = 8.5 nM)- and time-dependent (t_1/2 = 3.5 min) manner. Both fMLP-induced AA release and leukotriene C₄ (LTC₄) secretion were inhibited concentration dependently by arachidonic trifluoromethyl ketone, a cytosolic PLA₂ (cPLA₂) inhibitor; however, inhibition of neither the 14-kDa secretory phospholipase A₂ by 3-(3-acetamide-1-benzyl-2-ethylindolyl-5-oxy)propanephosphonic acid nor cytosolic Ca²⁺-independent phospholipase A₂ inhibition by bromoenol lactone blocked hydrolysis of AA or subsequent leukotriene synthesis. Pretreatment of eosinophils with a mitogen-activated protein/extracellular signal-regulated protein kinase (ERK) kinase inhibitor, U0126, or a p38 MAPK inhibitor, SB203580, suppressed both AA production and LTC₄ release. fMLP induced phosphorylation of MAPK isoforms, ERK1/2 and p38, which were evident after 30 s, maximal at 1–5 min, and declined thereafter. fMLP stimulation also increased cPLA₂ activity in eosinophils, which was inhibited completely by 30 µM arachidonic trifluoromethyl ketone. Preincubation of eosinophils with U0126 or SB203580 blocked fMLP-enhanced cPLA₂ activity. Furthermore, inhibition of Ras, an upstream GTP-binding protein of ERK, also suppressed fMLP-stimulated AA release. These findings demonstrate that cPLA₂ activation causes AA hydrolysis and LTC₄ secretion. We also find that cPLA₂ activation caused by fMLP occurs subsequent to and is dependent upon ERK1/2 and p38 MAPK activation. Other PLA₂ isoforms native to human eosinophils possess no significant activity in the stimulated production of AA or LTC₄.

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