We examined the ability of two recombinant human cytokines, granulocyte-macrophage colony-stimulating factor (rHu-GM-CSF) and interferon-gamma (rHu-IFN-gamma) to activate antibacterial mechanisms in human pulmonary macrophages (PM) and peripheral blood monocytes (PBM). Growth of Legionella pneumophila (LP) was assessed in PM or PBM which had been exposed to either rHu-IFN-gamma (500-1000 u/ml) or rHu-GM-CSF (1 to 10,000 u/ml). In both PM and PBM exposed to 500 u/ml rHu-IFN-gamma, growth of LP was reduced compared to cells exposed to media alone. By comparison, exposure of these cell types to rHu-GM-CSF had no detectable effect on bacterial replication. In order to investigate potential mechanisms accounting for this observation, the effect of these cytokines on the hydrogen peroxide (H2O2)-releasing capacity of cells was studied. Exposure of PM and PBM to rHu-IFN-gamma (500 to 1000 u/ml) resulted in increased production of H2O2 triggered by phorbol myristate acetate; when subjected to the same experimental conditions, rHu-GM-CSF-exposed cells exhibited no increase in H2O2 production. To further clarify the role of rHu-IFN-gamma-induced augmentation of oxidative metabolism on cellular inhibition of bacterial growth, an amount of catalase capable of completely neutralizing extracellular H2O2 was added to cells before and during infection. This did not abrogate the antibacterial activity of rHu-IFN-gamma. These studies demonstrate that rHu-IFN-gamma but not rHu-GM-CSF is capable of augmenting the capacity of PM and PBM to restrict LP growth. These data suggest that the antibacterial activity of rHu-IFN-gamma in this system may involve oxidative as well as nonoxidative mechanisms.