Interferon-y and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages*
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-y (rIFN-y) and recombinant tumor necrosis factor (rTNF) synergize to induce nitrite (NOz-) and nitrate (NO3-) synthesis from L-arginine as well as to cause inhibition of the iron-dependent enzyme aconitase in macrophages. Unlike rTNF, recombinant interleukin 1 (rIL 1) and rIL 6/B cell stimulatory factor 2 (rIL61BSF-2) did not act as cofactors when added to macrophages in the presence of rIFN-y. rIFN-y plus MDP induced the L-arginine-dependent effector mechanism in murine macrophages. However, induction by rIFN-y plus MDP was inhibited by anti-rTNF antibodies which suppressed both NO2-/NO3-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-y. In contrast, anti-rTNF antibodies did not fully suppress the effect of combining rIFN-y 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-y and TNF can modulate macrophage functions involved in the control of cell proliferation.