Synergistic interactions between IFN-gamma and IFN-beta in priming murine macrophages for tumor cell killing

The ability of MuIFN-beta and MuIFN-gamma to potentiate the development of tumoricidal activity in proteose peptone-elicited murine peritoneal macrophages was investigated. Macrophages were stimulated with increasing concentrations of either MuIFN-beta or MuIFN-gamma, alone and in combination, in the presence of 1 ng/ml lipopolysaccharide (LPS). The priming activities attributable to the interferons (IFNs) were quantified using the dose-response curves obtained for these samples. The priming activity observed for mixtures of MuIFN-beta and MuIFN-gamma was greater than that expected if MuIFN-beta and MuIFN-gamma had acted in an additive manner. Isobologram analysis of data obtained when macrophages were stimulated with combinations of IFNs demonstrated that MuIFN-beta and MuIFN-gamma acted synergistically to prime macrophages for tumor cell killing. The greatest degree of synergy was observed when macrophages were stimulated with suboptimal and nearly equivalent concentrations of each class of IFN. Further studies demonstrated that macrophages stimulated with combinations of MuIFN-beta and MuIFN-gamma were more sensitive to the trigger signal provided by LPS than were cells primed with either IFN alone. Thus, the synergistic effects observed were quantitative in nature in that macrophages perceived combinations of MuIFN-beta and MuIFN-gamma as having higher priming activities than expected.