Effect of recombinant tumor necrosis factor on tumoricidal activation of murine macrophages: synergism between tumor necrosis factor and gamma-interferon

Abstract

The activation of tumoricidal murine macrophages by recombinant human tumor necrosis factor (rH-TNF) alone or in combination with recombinant murine gamma-interferon (rM-IFN-gamma) was examined. When used alone, rH-TNF (10(-1)-10(5) units/ml) did not induce macrophage tumoricidal activity against TNF-insensitive P815 mastocytoma cells. Combining rH-TNF with rM-IFN-gamma resulted in the synergistic induction of tumoricidal activity in resident peritoneal macrophages. This synergistic effect was not due to contaminating bacterial lipopolysaccharide. A comparative study using recombinant murine tumor necrosis factor (rM-TNF) showed that rM-TNF alone also could not stimulate murine macrophages and there was no significant difference between effects of rM-TNF and rH-TNF on macrophage activation in the presence of rM-IFN-gamma. In experiments comparing sequential to simultaneous exposure of macrophages to rH-TNF and rM-IFN-gamma, it was found that: (a) when macrophages are primed with rM-IFN-gamma, rH-TNF serves only as a very weak triggering signal for tumoricidal activation; and (b) marked activation is obtained only when macrophages are exposed to the two cytokines simultaneously. These results suggest that TNF has an autocrine regulatory function in concert with lymphokines in macrophage-mediated host defense against tumors.