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-gamma (IFN-gamma) and lipopolysaccharide (LPS). Macrophages stimulated with IFN-gamma 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-alpha (TNF alpha)-mediated cytolysis by macrophages. Therefore, the purpose of this study was to determine whether PAF, in comparison with IFN-gamma and LPS, could stimulate macrophages for both TNF alpha- and non-TNF alpha-mediated tumoricidal activity. For this, the activation of macrophages for a cytolytic response was characterized by the production of TNF alpha and nitric oxide (NO2-), as well as, their ability to kill select tumor cells. PAF together with IFN-gamma stimulated macrophage secretion of NO2-. In addition, PAF enhanced IFN-gamma- and LPS-stimulated NO2- production. PAF, together with IFN-gamma, also activated macrophages for tumoricidal activity against TNF alpha-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-gamma. Moreover, PAF enhanced macrophage tumoricidal activity when added with LPS and IFN-gamma. With respect to TNF alpha production, macrophages activated with high concentrations of PAF stimulated significant levels of TNF alpha 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 TNF alpha-sensitive tumor cell. In addition, PAF significantly enhanced LPS-induced TNF alpha production. Thus, PAF can play a modulatory role in the activation for non-TNF alpha-mediated tumoricidal activity of macrophages.