Interferon‐γ and tumor necrosis factor induce the L‐arginine‐dependent cytotoxic effector mechanism in murine macrophages*

Abstract

We tested several monokines and muramyl dipeptide (MDP) to determine whether they induce the L‐arginine‐dependent effector mechanism in cultured murine macrophages. Recombinant interferon‐γ (rIFN‐γ) and recombinant tumor necrosis factor (rTNF) synergize to induce nitrite (NO 2−) and nitrate (NO 3−) synthesis from L‐arginine as well as to cause inhibition of the iron‐dependent enzyme aconitase in macrophages. Unlike rTNF, recombinant interleukin 1 (rIL1) and rIL6/B cell stimulatory factor 2 (rIL 6/BSF‐2) did not act as cofactors when added to macrophages in the presence of rIFN‐γ. rIFN‐γ plus MDP induced the L‐arginine‐dependent effector mechanism in murine macrophages. However, induction by rIFN‐γ plus MDP was inhibited by anti‐rTNF antibodies which suppressed both NO 2−/NO 3− synthesis and aconitase inhibition. This result indicates that endogenously produced TNF is involved in the induction of the L‐arginine‐dependent effector mechanism when MDP is the co‐stimulant with rIFN‐γ. In contrast, anti‐rTNF antibodies did not fully suppress the effect of combining rIFN‐γ and lipopolysaccharide, suggesting that, in this case, activation of the L‐arginine‐dependent effector pathway may involve more than induction of TNF synthesis by the macrophages. These results provide information, at a biochemical level, on a mechanism through which combination of IFN‐γ and TNF can modulate macrophage functions involved in the control of cell proliferation.