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Independent Functioning of Cytosolic Phospholipase A₂ and Phospholipase D₁ in Trp-Lys-Tyr-Met-Val-D-Met-Induced Superoxide Generation in Human Monocytes¹

Department of Life Science, Pohang University of Science and Technology, Pohang, Korea

Recently, a novel peptide (Trp-Lys-Tyr-Met-Val-D-Met, WKYMVm) has been shown to induce superoxide generation in human monocytes. The peptide stimulated phospholipase A₂ (PLA₂) activity in a concentration- and time-dependent manner. Superoxide generation as well as arachidonic acid (AA) release evoked by treatment with WKYMVm could be almost completely blocked by pretreatment of the cells with cytosolic PLA₂ (cPLA₂)-specific inhibitors. The involvement of cPLA₂ in the peptide-induced AA release was further supported by translocation of cPLA₂ to the nuclear membrane of monocytes incubated with WKYMVm. WKYMVm-induced phosphatidylbutanol formation was completely abolished by pretreatment with PKC inhibitors. Immunoblot showed that monocytes express phospholipase D₁ (PLD₁), but not PLD₂. GF109203X as well as butan-1-ol inhibited peptide-induced superoxide generation in monocytes. Furthermore, the interrelationship between the two phospholipases, cPLA₂ and PLD₁, and upstream signaling molecules involved in WKYMVm-dependent activation was investigated. The inhibition of cPLA₂ did not blunt peptide-stimulated PLD1 activation or vice versa. Intracellular Ca²⁺ mobilization was indispensable for the activation of PLD₁ as well as cPLA₂. The WKYMVm-dependent stimulation of cPLA₂ activity was partially dependent on the activation of PKC and mitogen-activated protein kinase, while PKC activation, but not mitogen-activated protein kinase activation, was an essential prerequisite for stimulation of PLD₁. Taken together, activation of the two phospholipases, which are absolutely required for superoxide generation, takes place through independent signaling pathways that diverge from a common pathway at a point downstream of Ca²⁺.