The activation of tumoricidal murine macrophages by recombinant human tumor necrosis factor (rH-TNF) alone or in combination with recombinant murine γ-interferon (rM-IFN-γ) was examined. When used alone, rH-TNF (10-1-105 units/ml) did not induce macrophage tumoricidal activity against TNF-insensitive P815 mastocytoma cells. Combining rH-TNF with rM-IFN-γ 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-γ. In experiments comparing sequential to simultaneous exposure of macrophages to rH-TNF and rM-IFN-γ, it was found that: (a) when macrophages are primed with rM-IFN-γ, 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.

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Supported in part by the Asahi Chemical Industry Co., Ltd.; by U. S. Public Health Service Grants CA-24538, CA-15142, and CA-09072 awarded by the National Cancer Institute, Department of Health and Human Services; and by Grant IFN-18 awarded by the American Cancer Society.

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