The effects of three lipid peroxidation end-products, 4-hydroxynonenal (HNE), 2-nonenal (NE) and nonanal, on phosphoinositide-specific phospholipase C (PL-C) activity were studied in HL-60 cells. Enzymatic activity was determined by measuring the amounts of inositol-P3 (Ins-P3) produced by the cells incubated at 37 degrees C in the presence of the various compounds. HNE was shown to activate PL-C at concentrations of between 10(-8) and 10(-6) M; 10(-9) and 10(-8) M of NE also strongly stimulated PL-C. In contrast, nonanal failed to modify enzymatic activity. The concentrations of HNE and NE active on PL-C showed good correspondence with those that have been reported to be chemotactic towards rat neutrophils. The pretreatment of cells with 1 microM pertussis toxin completely prevented the increase of Ins-P3 production induced by HNE and NE. Maximal PL-C stimulation was produced by 10 nM NE; the degree of inositol-P3 production induced by the simultaneous addition of an equimolar dose of HNE was not significantly different from the activity value induced by NE alone, suggesting a possible competition between the two compounds. The data indicate that both HNE and NE share a common mechanism of action which, as with other better-known chemoattractants, involves PL-C activation through a G regulatory protein.