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 stra ins (Luk-PV) on the generation of Leukotriene B-4 (LTB(4)) and its met abolites 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-per formance liquid chromatography analysis. In this regard, the S and F c omponents of leukocidin acted synergistically. The calcium ionophore A 23187 induced LTB(4) generation, and the metabolism of exogenously add ed LTB(4) into biologically less active omega-oxidated compounds was s ignificantly decreased after leukocidin exposure. Priming of PMNs with granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF pr ior to leukocidin exposure substantially increased toxin- and calcium ionophore A23187-induced LTB(4) formation. The inhibitory effects of l eukocidin 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 fact ors such as GM-CSF or G-CSF in the microenvironment of an inflammatory focus determines the pathophysiological effects induced by S. aureus leukocidin.