Phospholipase A(2) is involved in the mechanism of activation of neutrophils by polychlorinated biphenyls

Aroclor 1242, a mixture of polychlorinated biphenyls (PCBs), activates neutrophils to produce superoxide anion (O-2(-)) by a mechanism that involves phospholipase C-dependent hydrolysis of membrane phosphoinositides; however, subsequent signal transduction mechanisms are unknown. We undertook this study to determine whether phospholipase A(2)-dependent release of arachidonic acid is involved in PCB-induced O-2(-) production. We measured O-2(-) production. We measured O-2(-) production in vitro in glycogen - elicited, rat neutrophils in the presence and absence of the inhibitors of phospholipase A(2): quinacrine, 4- bromophenacyl bromide (BPB), and manoalide. All three agents significantly decreased the amount of O-2(-) detected during stimulation of neutrophils with Aroclor 1242. Similar inhibition occurred when neutrophils were activated with the classical stimuli, formyl - methionyl - leucyl - phenylalanine (fMLP) or phorbol myristate acetate. The effects of BPB and manoalide were not a result of cytotoxicity or other nonspecific effects, although data suggest that quinacrine is an O-2(-) scavenger. Significant release of H-3-arachidonate. Aspirin, zileuton, or WEB 2086 did not effect Aroclor 1242-induced O-2(-) production, suggesting that eicosanoids and platelet - activating factor are not needed for neutrophil activation by PCBs. Activation of phospholipase A(2) and O-2(-) production do not appear to involve the Ah receptor because a congener with low affinity, but not one with high affinity for this receptor, stimulated the release of arachidonic acid and O-2(-). These data suggest that Aroclor 1242 stimulates neutrophils to produce O-2(-) by a mechanism that involves phospholipase A(2)- dependent release of arachidonic acid.