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PMID: 2497225 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of experimental medicine ·Vol. 169 ·No. 5 ·1989-05-01 ·Pages 1543-55

Stuehr DJ, Nathan CF

Abstract

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.

MeSH Terms
Animals Arginine/metabolism Cell Survival/drug effects Cells, Cultured DNA/biosynthesis Free Radicals Interferon-gamma/pharmacology Leukemia L1210/metabolism,pathology Lipopolysaccharides/pharmacology Macrophage Activation Macrophages/metabolism Mice Myoglobin/metabolism Nitrates/metabolism Nitric Oxide/metabolism,pharmacology Nitrogen Dioxide/metabolism Oxygen Consumption/drug effects
Chemicals
Free Radicals Lipopolysaccharides Myoglobin Nitrates Nitric Oxide Interferon-gamma DNA Arginine Nitrogen Dioxide
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Stuehr D J
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Nathan C F
References (44)
44 references, click to expand
  1. Oxidation of microbial iron-sulfur centers by the myeloperoxidase-H2O2-halide antimicrobial system.
    Infect Immun. 1985 Mar;47(3):613-8 PMID: 2982737
  2. 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):6369-73 PMID: 2819872
  3. Role of interleukin 1 in promoting human monocyte-mediated tumor cytotoxicity.
    J Immunol. 1985 Jul;135(1):314-20 PMID: 3873493
  4. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate.
    Biochemistry. 1988 Nov 29;27(24):8706-11 PMID: 3242600
  5. 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):866-79 PMID: 2890446
  6. Hydrogenase activity in Azospirillum brasilense is inhibited by nitrite, nitric oxide, carbon monoxide, and acetylene.
    J Bacteriol. 1984 Oct;160(1):103-6 PMID: 6384189
  7. 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):708-16 PMID: 2983068
  8. 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 PMID: 6798167
  9. An L-arginine-dependent mechanism mediates Kupffer cell inhibition of hepatocyte protein synthesis in vitro.
    J Exp Med. 1989 Apr 1;169(4):1467-72 PMID: 2926330
  10. 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):5233-7 PMID: 3487788
  11. Nitric oxide: a cytotoxic activated macrophage effector molecule.
    Biochem Biophys Res Commun. 1988 Nov 30;157(1):87-94 PMID: 3196352
  12. Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-gamma.
    J Immunol. 1987 Jul 15;139(2):518-25 PMID: 3110273
  13. 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):2407-12 PMID: 3139757
  14. 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):833-40 PMID: 188423
  15. THE INHIBITION OF HYDROGENASE BY NITRIC OXIDE.
    Proc Natl Acad Sci U S A. 1954 Apr;40(4):225-7 PMID: 16589460
  16. 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):7738-42 PMID: 3906650
  17. Inactivation of bacteriophage phi-X-174 by sublethal nitrous acid--produced lesions.
    Biochem Biophys Res Commun. 1970 Jun 5;39(5):809-15 PMID: 5423823
  18. The tyrosyl free radical in ribonucleotide reductase.
    Environ Health Perspect. 1985 Dec;64:139-49 PMID: 3007085
  19. Comparison of superoxide with other reducing agents in the biological production of hydroxyl radicals.
    Biochem J. 1979 Aug 15;182(2):625-8 PMID: 41521
  20. 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):2447-55 PMID: 4336375
  21. 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 PMID: 2888663
  22. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.
    J Cell Biol. 1982 Nov;95(2 Pt 1):527-35 PMID: 6292238
  23. Mitochondrial iron loss from leukemia cells injured by macrophages. A possible mechanism for electron transport chain defects.
    J Immunol. 1988 Aug 15;141(4):1311-7 PMID: 3397540
  24. The effects of activated macrophages on tumor target cells: escape from cytostasis.
    Cell Immunol. 1976 Aug;25(2):279-93 PMID: 821620
  25. Injury of neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration.
    J Clin Invest. 1980 Feb;65(2):357-70 PMID: 7356685
  26. Stoichiometry of the reaction of oxyhemoglobin with nitrite.
    Biochim Biophys Acta. 1979 Nov 23;581(1):184-8 PMID: 41590
  27. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite.
    Science. 1987 Jan 23;235(4787):473-6 PMID: 2432665
  28. Resistance of human tumor cells in vitro to oxidative cytolysis.
    J Clin Invest. 1985 Jul;76(1):80-6 PMID: 2991343
  29. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.
    Nature. 1986 Apr 3-9;320(6061):454-6 PMID: 3007998
  30. Factors affecting the bacteriostatic action of sodium nitrite.
    Appl Microbiol. 1955 May;3(3):154-9 PMID: 14377383
  31. 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):831-4 PMID: 6769392
  32. 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):739-49 PMID: 6115052
  33. 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):208-12 PMID: 187114
  34. Hydrogen peroxide release from mouse peritoneal macrophages: dependence on sequential activation and triggering.
    J Exp Med. 1977 Dec 1;146(6):1648-62 PMID: 925614
  35. Endocytosis of red blood cells or haemoglobin by activated macrophages inhibits their tumoricidal effect.
    Nature. 1977 Sep 15;269(5625):245-7 PMID: 563513
  36. Secretion of oxygen intermediates: role in effector functions of activated macrophages.
    Fed Proc. 1982 Apr;41(6):2206-11 PMID: 6281078
  37. The effect of nitric oxide on bacteria.
    Appl Microbiol. 1962 May;10:185-9 PMID: 13911227
  38. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.
    Nature. 1987 Jun 11-17;327(6122):524-6 PMID: 3495737
  39. Trapping of nitric oxide produced during denitrification by extracellular hemoglobin.
    J Biol Chem. 1988 Feb 15;263(5):2316-23 PMID: 3339013
  40. The cell biology of macrophage activation.
    Annu Rev Immunol. 1984;2:283-318 PMID: 6100475
  41. 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):1083-90 PMID: 3135320
  42. 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):1011-20 PMID: 2784476
  43. Nitrate biosynthesis in man.
    Proc Natl Acad Sci U S A. 1981 Dec;78(12):7764-8 PMID: 6950416
  44. 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):790-7 PMID: 3745439
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.169.5.1543
Published
1989-05-01
Pages
1543-55
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2189318
Subset
IM
Grants
NCI NIH HHS · CA-43610 · United States
External Links
PubMed source DOI: 10.1084/jem.169.5.1543 PMC Full Text View journal details
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