Addition of submicromolar concentrations of arachidonic acid (AA) to human neutrophils induced a 2-fold increase in the activity of a cytosolic phospholipase A (PLA) when measured using sonicated vesicles of 1-stearoyl-2-[C]arachidonoylphosphatidylcholine as substrate. A similar increase in cytosolic PLA activity was induced by stimulation of neutrophils with leukotriene B (LTB), 5-oxoeicosatetraenoic acid, or 5-hydroxyeicosatetraenoic acid (5-HETE). LTB was the most potent of the agonists, showing maximal effect at 1 nM. Inhibition of 5-lipoxygenase with either eicosatetraynoic acid or zileuton prevented the AA-induced increase in PLA activity but had no effect on the response induced by LTB. Furthermore, pretreatment of neutrophils with a LTB-receptor antagonist, LY 255283, blocked the AA- and LTB-induced activation of PLA but did not influence the action of 5-HETE. Treatment of neutrophils with pancreatic PLA also induced an increase in the activity of the cytosolic PLA; this response was inhibited by both eicosatetraynoic acid or LY 255283.

The increases in PLA activity in response to stimulation correlated with a shift in electrophoretic mobility of the 85-kDa PLA, as determined by Western blot analysis, suggesting that phosphorylation of the 85-kDa PLA likely underlies its increase in catalytic activity. Although stimulation of neutrophils with individual lipoxygenase metabolites did not induce significant mobilization of endogenous AA, they greatly enhanced the N-formylmethionyl-leucyl-phenylalanine-induced mobilization of AA as determined by mass spectrometry analysis. Our findings support a positive-feedback model in which stimulus-induced release of AA or exocytosis of secretory PLA modulate the activity of the cytosolic 85-kDa PLA by initiating the formation of LTB. The nascent LTB is then released to act on the LTB receptor and thereby promote further activation of the 85-kDa PLA. Since 5-HETE and LTB are known to prime the synthesis of platelet-activating factor, the findings suggest that 85-kDa PLA plays a role in platelet-activating factor synthesis.

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