The Induction and Augmentation of Macrophage Tumoricidal Responses by Platelet-Activating Factor

Platelet-activating factor (PAF) has previously been shown to stimulate intracellular signal transductional events similar to the macrophage tumoricidal activators interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Macrophages stimulated with IFN-γ and LPS utilize various cytolytic mediators in order to kill tumor cells. However, PAF has been shown to only induce and enhance tumor necrosis factor-α (TNFα)-mediated cytolysis by macrophages. Therefore, the purpose of this study was to determine whether PAF, in comparison with IFN-γ and LPS, could stimulate macrophages for both TNFγ- and non-TNFγ-mediated tumoricidal activity. For this, the activation of macrophages for a cytolytic response was characterized by the production of TNFγ and nitric oxide (NO^- ₂), as well as, their ability to kill select tumor cells. PAF together with IFN-γ stimulated macrophage secretion of NO^- ₂. In addition, PAF enhanced IFN-γ- and LPS-stimulated NO^- ₂ production. PAF, together with IFN-γ, also activated macrophages for tumoricidal activity against TNFγ-resistant tumor cells. In assays to determine the temporal sequence of activation, increased tumor cell cytolysis was observed only when macrophages were first treated with IFN-γ. Moreover, PAF enhanced macrophage tumoricidal activity when added with LPS and IFN-γ. With respect to TNFγ production, macrophages activated with high concentrations of PAF stimulated significant levels of TNFγ compared to macrophages without PAF. A similar level was observed following multiple additions of a lower concentration of PAF, Also, PAF induced macrophage cytolytic activity against a TNFγ-sensitive tumor cell. In addition, PAF significantly enhanced LPS-induced TNFα production. Thus, PAF can play a modulatory role in the activation for non-TNFγ-mediated tumoricidal activity of macrophages.