Platelet-activating factor-induced hydrolysis of phosphatidylinositol 4,5-bisphosphate stimulates the production of reactive oxygen intermediates in macrophages

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Abstract
To investigate the relationship between inositol lipid hydrolysis and reactive oxygen-intermediate (ROI) production in macrophages we have examined the effect of platelet-activating factor (PAF) on normal bone marrow-derived macrophages. Addition of PAF to macrophages prelabelled with [3H]inositol caused a marked and rapid increase in [3H]inositol trisphosphate levels. Similarly when PAF was added to [3H]-glycerol prelabelled macrophages there was a rapid increase in 1,2-diacyl[3H]glycerol levels. These events preceded any increase in the rate of PAF-stimulated ROI production by a discernible period of several seconds. Increasing concentrations of PAF led to a markedly similar increase in both ROI production and [3H]inositol lipid hydrolysis suggesting that inositol lipid hydrolysis may lead to the generation of ROI in macrophages with phorbol esters was shown to inhibit both PAF-stimulated [3H]inositol phosphate production and ROI production to a markedly similar degree. Similarly pertussis toxin inhibited both PAF-stimulated ROI production and [3H]inositol phosphate production. Phorbol esters were shown to activate ROI production in normal bone marrow-derived macrophages whereas the Ca2+ ionophore, A23187, did not. These experiments suggest that PAF stimulates a pertussis toxin-sensitive activation of inositol lipid hydrolysis leading to the formation of inositol trisphosphate and diacylglycerol. The diacylglycerol formed can then activate protein kinase C leading to the stimulation of ROI production in normal bone marrow-derived macrophages.

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