Expression of phospholipases A 2 in primary human lung macrophages : Role of cytosolic phospholipase A 2-α in arachidonic acid release and platelet activating factor synthesis

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Macrophages are a major source of lipid mediators in the human lung. Expression and contribution of cytosolic (cPLA 2) and secreted phospholipases A 2 (sPLA 2) to the generation of lipid mediators in human macrophages are unclear. We investigated the expression and role of different PLA 2s in the production of lipid mediators in primary human lung macrophages. Macrophages express the alpha, but not the zeta isoform of group IV and group VIA cPLA 2 (iPLA 2). Two structurally-divergent inhibitors of group IV cPLA 2 completely block arachidonic acid release by macrophages in response to non-physiological (Ca 2+ ionophores and phorbol esters) and physiological agonists (lipopolysaccharide and Mycobacterium protein derivative). These inhibitors also reduce by 70% the synthesis of platelet-activating factor by activated macrophages. Among the full set of human sPLA 2s, macrophages express group IIA, IID, IIE, IIF, V, X and XIIA, but not group IB and III enzymes. Me-Indoxam, a potent and cell impermeable inhibitor of several sPLA 2s, has no effect on arachidonate release or platelet-activating factor production. Agonist-induced exocytosis is not influenced by cPLA 2 inhibitors at concentrations that block arachidonic acid release. Our results indicate that human macrophages express cPLA 2-alpha, iPLA 2 and several sPLA 2s. Cytosolic PLA 2-alpha is the major enzyme responsible for lipid mediator production in human macrophages.