LEUKOTRIENE B-4 GENERATION AND DNA FRAGMENTATION INDUCED BY LEUKOCIDIN FROM STAPHYLOCOCCUS-AUREUS - PROTECTIVE ROLE OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF) AND G-CSF FOR HUMAN NEUTROPHILS

We studied the effect of leukocidin from Staphylococcus aureus V8 strains (Luk-PV) on the generation of Leukotriene B-4 (LTB(4)) and its metabolites from human polymorphonuclear neutrophils (PMNs). Significant amounts of LTB(4) were generated by PMNs after leukocidin exposure in a time- and dose-dependent manner, as shown by reversed-phase high-performance liquid chromatography analysis. In this regard, the S and F components of leukocidin acted synergistically. The calcium ionophore A23187 induced LTB(4) generation, and the metabolism of exogenously added LTB(4) into biologically less active omega-oxidated compounds was significantly decreased after leukocidin exposure. Priming of PMNs with granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF prior to leukocidin exposure substantially increased toxin- and calcium ionophore A23187-induced LTB(4) formation. The inhibitory effects of leukocidin on mediator release were accompanied by membrane damage and DNA fragmentation, which were both restored after pretreatment with GM-CSF. The data suggest that the presence of costimulatory priming factors such as GM-CSF or G-CSF in the microenvironment of an inflammatory focus determines the pathophysiological effects induced by S. aureus leukocidin.