NO is not sufficient to explain maximal cytotoxicity of tumoricidal macrophages against an NO-sensitive cell line

Abstract: Nitric oxide (NO) is a macrophage cyto-toxic effector. Results presented here, however, demonstrate that NO does not fully explain macro-phage cytotoxicity against NO-sensitive cells because ( 1) inhibition of NO production by activated macro-phages reduces, not eliminates, cytotoxicity; (2) NO produced chemically in amounts equimolar to those released from macrophages fails to lyse P8 1 5 cells; and (3) macrophages isolated from wounds 10 days after injury generate NOjust as tumoricidal activated macrophages but are not tumor cytotoxic. The noncytotoxic nature of these wound-derived macro-phages is not explained by the release of inactive forms of NO, because they suppress lymphocyte proliferation in an NO-dependent manner, nor by the production of cytoprotective molecules, because their addition to activated macrophage-tumor cell cocultures does not quench cytotoxicity. Interest-ingly, cytotoxicity can be aroused in day 1 0 wound-derived macrophages by culture with lipopolysaccharide, and macrophages harvested ear-her in the development of the wound are cytotoxic. By generating NO but not killing an NO-sensitive cell, day 10 wound-derived macrophages demonstrate that NO production is not sufficient to account for the killing ofan NO-sensitive tumor by macrophages