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J Exp Med. 1989 May 1; 169(5): 1543–1555.
PMCID: PMC2189318

Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells


A metabolic pathway of activated macrophages (M phi) involving oxidation of the guanido nitrogens of L-arginine is required for inhibition of growth and respiration of some target cells. The goal of this study was to identify the M phi metabolite(s) that induce these injuries. The stable products of the L-arginine pathway, NO2- and NO3-, were incapable of causing cytostasis under coculture conditions. However, NO2- became cytostatic upon mild acidification, which favors its transformation into nitrogen oxides of greater reactivity. This suggested that NO. (and/or NO2), recently identified as an M phi metabolite of L-arginine, could be a mediator. Authentic NO. caused cytostasis and respiratory inhibition in L1210 cells in a dose- dependent manner. The mitochondrial lesions caused by NO. were confined to complex 1 and 2, a pattern of injury identical to that seen after coculture with activated M phi. Inclusion of NO. scavenger systems prevented cytostasis from developing in M phi-L1210 cocultures. Thus, M phi-generated NO. can account for L-arginine-dependent cytostasis and respiratory inhibition.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adams DO, Hamilton TA. The cell biology of macrophage activation. Annu Rev Immunol. 1984;2:283–318. [PubMed]
  • Nathan CF. Secretion of oxygen intermediates: role in effector functions of activated macrophages. Fed Proc. 1982 Apr;41(6):2206–2211. [PubMed]
  • Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H. Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5233–5237. [PMC free article] [PubMed]
  • Onozaki K, Matsushima K, Kleinerman ES, Saito T, Oppenheim JJ. Role of interleukin 1 in promoting human monocyte-mediated tumor cytotoxicity. J Immunol. 1985 Jul;135(1):314–320. [PubMed]
  • Hibbs JB, Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. [PubMed]
  • Stuehr DJ, Gross SS, Sakuma I, Levi R, Nathan CF. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J Exp Med. 1989 Mar 1;169(3):1011–1020. [PMC free article] [PubMed]
  • Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987 Dec;61(6):866–879. [PubMed]
  • Drapier JC, Hibbs JB., Jr Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. J Clin Invest. 1986 Sep;78(3):790–797. [PMC free article] [PubMed]
  • Granger DL, Lehninger AL. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J Cell Biol. 1982 Nov;95(2 Pt 1):527–535. [PMC free article] [PubMed]
  • Green LC, Ruiz de Luzuriaga K, Wagner DA, Rand W, Istfan N, Young VR, Tannenbaum SR. Nitrate biosynthesis in man. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7764–7768. [PMC free article] [PubMed]
  • CASTELLANI AG, NIVEN CF., Jr Factors affecting the bacteriostatic action of sodium nitrite. Appl Microbiol. 1955 May;3(3):154–159. [PMC free article] [PubMed]
  • SHANK JL, SILLIKER JH, HARPER RH. The effect of nitric oxide on bacteria. Appl Microbiol. 1962 May;10:185–189. [PMC free article] [PubMed]
  • Lytle CD, Ginoza W. Inactivation of bacteriophage phi-X-174 by sublethal nitrous acid--produced lesions. Biochem Biophys Res Commun. 1970 Jun 5;39(5):809–815. [PubMed]
  • Krahenbuhl JL, Lambert LH, Jr, Remington JS. The effects of activated macrophages on tumor target cells: escape from cytostasis. Cell Immunol. 1976 Aug;25(2):279–293. [PubMed]
  • Granger DL, Taintor RR, Cook JL, Hibbs JB., Jr Injury of neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration. J Clin Invest. 1980 Feb;65(2):357–370. [PMC free article] [PubMed]
  • Winterbourn CC. Comparison of superoxide with other reducing agents in the biological production of hydroxyl radicals. Biochem J. 1979 Aug 15;182(2):625–628. [PMC free article] [PubMed]
  • O'Donnell-Tormey J, DeBoer CJ, Nathan CF. Resistance of human tumor cells in vitro to oxidative cytolysis. J Clin Invest. 1985 Jul;76(1):80–86. [PMC free article] [PubMed]
  • Yonetani T, Yamamoto H, Erman JE, Leigh JS, Jr, Reed GH. Electromagnetic properties of hemoproteins. V. Optical and electron paramagnetic resonance characteristics of nitric oxide derivatives of metalloporphyrin-apohemoprotein complexes. J Biol Chem. 1972 Apr 25;247(8):2447–2455. [PubMed]
  • Goretski J, Hollocher TC. Trapping of nitric oxide produced during denitrification by extracellular hemoglobin. J Biol Chem. 1988 Feb 15;263(5):2316–2323. [PubMed]
  • Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther. 1985 Mar;232(3):708–716. [PubMed]
  • Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. [PubMed]
  • Salerno JC, Ohnishi T. Tetranuclear and binuclear iron-sulfur clusters in succinate dehydrogenase: a method of iron quantitation by formation of paramagnetic complexes. Biochem Biophys Res Commun. 1976 Dec 6;73(3):833–840. [PubMed]
  • Wharton M, Granger DL, Durack DT. Mitochondrial iron loss from leukemia cells injured by macrophages. A possible mechanism for electron transport chain defects. J Immunol. 1988 Aug 15;141(4):1311–1317. [PubMed]
  • Gräslund A, Sahlin M, Sjöberg BM. The tyrosyl free radical in ribonucleotide reductase. Environ Health Perspect. 1985 Dec;64:139–149. [PMC free article] [PubMed]
  • Weinberg JB, Hibbs JB., Jr Endocytosis of red blood cells or haemoglobin by activated macrophages inhibits their tumoricidal effect. Nature. 1977 Sep 15;269(5625):245–247. [PubMed]
  • Woods LF, Wood JM, Gibbs PA. the involvement of Nitric Oxide in the inhibition of the phosphoroclastic system in Clostridium sporogenes by sodium nitrite. J Gen Microbiol. 1981 Aug;125(2):399–406. [PubMed]
  • Tibelius KH, Knowles R. Hydrogenase activity in Azospirillum brasilense is inhibited by nitrite, nitric oxide, carbon monoxide, and acetylene. J Bacteriol. 1984 Oct;160(1):103–106. [PMC free article] [PubMed]
  • Krasna AI, Rittenberg D. THE INHIBITION OF HYDROGENASE BY NITRIC OXIDE. Proc Natl Acad Sci U S A. 1954 Apr;40(4):225–227. [PMC free article] [PubMed]
  • O'Leary V, Solberg M. Effect of sodium nitrite inhibition on intracellular thiol groups and on the activity of certain glycolytic enzymes in Clostridium perfringens. Appl Environ Microbiol. 1976 Feb;31(2):208–212. [PMC free article] [PubMed]
  • Yarbrough JM, Rake JB, Eagon RG. Bacterial inhibitory effects of nitrite: inhibition of active transport, but not of group translocation, and of intracellular enzymes. Appl Environ Microbiol. 1980 Apr;39(4):831–834. [PMC free article] [PubMed]
  • Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981 Sep;218(3):739–749. [PubMed]
  • Gryglewski RJ, Palmer RM, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature. 1986 Apr 3;320(6061):454–456. [PubMed]
  • Feelisch M, Noack EA. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol. 1987 Jul 2;139(1):19–30. [PubMed]
  • Ding AH, Nathan CF, Stuehr DJ. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed]
  • Stuehr DJ, Marletta MA. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7738–7742. [PMC free article] [PubMed]
  • Stuehr DJ, Marletta MA. Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-gamma. J Immunol. 1987 Jul 15;139(2):518–525. [PubMed]
  • Iyengar R, Stuehr DJ, Marletta MA. Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: precursors and role of the respiratory burst. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6369–6373. [PMC free article] [PubMed]
  • Nathan CF, Root RK. Hydrogen peroxide release from mouse peritoneal macrophages: dependence on sequential activation and triggering. J Exp Med. 1977 Dec 1;146(6):1648–1662. [PMC free article] [PubMed]
  • Rosen H, Klebanoff SJ. Oxidation of microbial iron-sulfur centers by the myeloperoxidase-H2O2-halide antimicrobial system. Infect Immun. 1985 Mar;47(3):613–618. [PMC free article] [PubMed]
  • Lu CY, Lombardi MJ, Shea CM, Dustin LB. High strength binding of P815 mastocytoma cells is not necessary for their lysis by macrophages which have been primed and triggered in vitro. J Immunol. 1988 Aug 15;141(4):1083–1090. [PubMed]
  • Kosaka H, Imaizumi K, Imai K, Tyuma I. Stoichiometry of the reaction of oxyhemoglobin with nitrite. Biochim Biophys Acta. 1979 Nov 23;581(1):184–188. [PubMed]
  • Billiar TR, Curran RD, Stuehr DJ, West MA, Bentz BG, Simmons RL. An L-arginine-dependent mechanism mediates Kupffer cell inhibition of hepatocyte protein synthesis in vitro. J Exp Med. 1989 Apr 1;169(4):1467–1472. [PMC free article] [PubMed]
  • Marletta MA, Yoon PS, Iyengar R, Leaf CD, Wishnok JS. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry. 1988 Nov 29;27(24):8706–8711. [PubMed]
  • Hibbs JB, Jr, Taintor RR, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30;157(1):87–94. [PubMed]

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