NO is not sufficient to explain maximal cytotoxicity of tumoricidal macrophages against an NO-sensitive cell line.
Nitric oxide (NO) is a macrophage cytotoxic effector. Results presented here, however, demonstrate that NO does not fully explain macrophage cytotoxicity against NO-sensitive cells because (1) inhibition of NO production by activated macrophages reduces, not eliminates, cytotoxicity; (2) NO produced chemically in amounts equimolar to those released from macrophages fails to lyse P815 cells; and (3) macrophages isolated from wounds 10 days after injury generate NO just as tumoricidal activated macrophages but are not tumor cytotoxic. The noncytotoxic nature of these wound-derived macrophages 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. Interestingly, cytotoxicity can be aroused in day 10 wound-derived macrophages by culture with lipopolysaccharide, and macrophages harvested earlier 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 of an NO-sensitive tumor by macrophages.
Mateo
R B
RB
Department of Surgery, Division of Surgical Research, Rhode Island Hospital, Providence 02903, USA.
Reichner
J S
JS
Albina
J E
JE
D000818:Animals; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D012515:Mast-Cell Sarcoma / Q000188:drug therapy; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology; D014947:Wounds and Injuries / Q000473:pathology
D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D010396:Penicillamine