Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1983 Oct 1;158(4):1160–1177. doi: 10.1084/jem.158.4.1160

Adenosine: a physiological modulator of superoxide anion generation by human neutrophils

PMCID: PMC2187367  PMID: 6311934

Abstract

The effects of adenosine were studied on human neutrophils with respect to their generation of superoxide anion, degranulation, and aggregation in response to soluble stimuli. Adenosine markedly inhibited superoxide anion generation by neutrophils stimulated with N-formyl methionyl leucyl phenylalanine (FMLP), concanavalin A (Con A), calcium ionophore A23187, and zymosan-treated serum; it inhibited this response to PMA to a far lesser extent. The effects of adenosine were evident at concentrations ranging from 1 to 1,000 microM with maximal inhibition at 100 microM. Cellular uptake of adenosine was not required for adenosine-induced inhibition since inhibition was maintained despite the addition of dipyridamole, which blocks nucleoside uptake. Nor was metabolism of adenosine required, since both deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl) adenine did not interfere with adenosine inhibition of superoxide anion generation. The finding that 2- chloroadenosine, which is not metabolized, resembled adenosine in its ability to inhibit superoxide anion generation added further evidence that adenosine metabolism was not required for inhibition of superoxide anion generation by neutrophils. Unexpectedly, endogenously generated adenosine was present in supernatants of neutrophil suspensions at 0.14- 0.28 microM. Removal of endogenous adenosine by incubation of neutrophils with exogenous adenosine deaminase (ADA) led to marked enhancement of superoxide anion generation in response to FMLP. Inactivation of ADA with DCF abrogated the enhancement of superoxide anion generation. Thus, the enhancement was not due to a nonspecific effect of added protein. Nor was the enhancement due to the generation of hypoxanthine or inosine by deamination of adenosine, since addition of these compounds did not affect neutrophil function. Adenosine did not significantly affect either aggregation or lysozyme release and only modestly affected beta-glucuronidase release by neutrophils stimulated with FMLP. These data indicate that adenosine (at concentrations that are present in plasma) acting via cell surface receptors is a specific modulator of superoxide anion generation by neutrophils.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baer H. P., Paton D. M. Adenosine receptors in smooth muscle and other tissues. Adv Cyclic Nucleotide Res. 1978;9:315–325. [PubMed] [Google Scholar]
  2. Berne R. M. The role of adenosine in the regulation of coronary blood flow. Circ Res. 1980 Dec;47(6):807–813. doi: 10.1161/01.res.47.6.807. [DOI] [PubMed] [Google Scholar]
  3. Borregaard N., Herlin T. Energy metabolism of human neutrophils during phagocytosis. J Clin Invest. 1982 Sep;70(3):550–557. doi: 10.1172/JCI110647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boxer L. A., Baehner R. L., Davis J. The effect of 2-deoxyglucose on guinea pig polymorphonuclear leukocyte phagocytosis. J Cell Physiol. 1977 Apr;91(1):89–102. doi: 10.1002/jcp.1040910110. [DOI] [PubMed] [Google Scholar]
  5. Brittinger G., Hirschhorn R., Douglas S. D., Weissmann G. Studies on lysosomes. XI. Characterization of a hydrolase-rich fraction from human lymphocytes. J Cell Biol. 1968 May;37(2):394–411. doi: 10.1083/jcb.37.2.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  7. CLARKE D. A., DAVOLL J., PHILIPS F. S., BROWN G. B. Enzymatic deamination and vasodepressor effects of adenosine analogs. J Pharmacol Exp Ther. 1952 Nov;106(3):291–302. [PubMed] [Google Scholar]
  8. Daly J. W., Bruns R. F., Snyder S. H. Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. Life Sci. 1981 May 11;28(19):2083–2097. doi: 10.1016/0024-3205(81)90614-7. [DOI] [PubMed] [Google Scholar]
  9. Goldstein I. M., Roos D., Kaplan H. B., Weissmann G. Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis. J Clin Invest. 1975 Nov;56(5):1155–1163. doi: 10.1172/JCI108191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hirschhorn R., Roegner-Maniscalco V., Kuritsky L., Rosen F. S. Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients. J Clin Invest. 1981 Dec;68(6):1387–1393. doi: 10.1172/JCI110389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hirschhorn R., Roegner V., Jenkins T., Seaman C., Piomelli S., Borkowsky W. Erythrocyte adenosine deaminase deficiency without immunodeficiency. Evidence for an unstable mutant enzyme. J Clin Invest. 1979 Oct;64(4):1130–1139. doi: 10.1172/JCI109552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hirschhorn R., Roegner V., Rubinstein A., Papageorgiou P. Plasma deoxyadenosine, adenosine, and erythrocyte deoxyATP are elevated at birth in an adenosine deaminase-deficient child. J Clin Invest. 1980 Mar;65(3):768–771. doi: 10.1172/JCI109725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Holgate S. T., Lewis R. A., Austen K. F. Role of adenylate cyclase in immunologic release of mediators from rat mast cells: agonist and antagonist effects of purine- and ribose-modified adenosine analogs. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6800–6804. doi: 10.1073/pnas.77.11.6800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaplan H. B., Edelson H. S., Friedman R., Weissmann G. The roles of degranulation and superoxide anion generation in neutrophil aggregation. Biochim Biophys Acta. 1982 Sep 13;721(1):55–63. doi: 10.1016/0167-4889(82)90023-4. [DOI] [PubMed] [Google Scholar]
  15. Lerner M. H., Lowy B. A. The formation of adenosine in rabbit liver and its possible role as a direct precursor of erythrocyte adenine nucleotides. J Biol Chem. 1974 Feb 10;249(3):959–966. [PubMed] [Google Scholar]
  16. Marone G., Findlay S. R., Lichtenstein L. M. Adenosine receptor on human basophils: modulation of histamine release. J Immunol. 1979 Oct;123(4):1473–1477. [PubMed] [Google Scholar]
  17. Marone G., Thomas L. L., Lichtenstein L. M. The role of agonists that activate adenylate cyclase in the control of cAMP metabolism and enzyme release by human polymorphonuclear leukocytes. J Immunol. 1980 Nov;125(5):2277–2283. [PubMed] [Google Scholar]
  18. Olaus T. H., Anand-Srivastava M. B., Johnson R. A. Regulation of hepatocyte cAMP and pyruvate kinase by site-specific analogs of adenosine. Mol Cell Endocrinol. 1982 May;26(3):269–279. doi: 10.1016/0303-7207(82)90116-2. [DOI] [PubMed] [Google Scholar]
  19. Pike M. C., Snyderman R. Transmethylation reactions regulate affinity and functional activity of chemotactic factor receptors on macrophages. Cell. 1982 Jan;28(1):107–114. doi: 10.1016/0092-8674(82)90380-4. [DOI] [PubMed] [Google Scholar]
  20. Sattin A., Rall T. W. The effect of adenosine and adenine nucleotides on the cyclic adenosine 3', 5'-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol. 1970 Jan;6(1):13–23. [PubMed] [Google Scholar]
  21. Schimmel R. J. Interactions between catecholamines, methyl xanthines and adenosine in regulation of cyclic AMP accumulation in hamster adipocytes. Biochim Biophys Acta. 1980 Apr 17;629(1):83–94. doi: 10.1016/0304-4165(80)90267-6. [DOI] [PubMed] [Google Scholar]
  22. Schwartz A. L., Stern R. C., Polmar S. H. Demonstration of adenosine receptor on human lymphocytes in vitro and its possible role in the adenosine deaminase-deficient form of severe combined immunodeficiency. Clin Immunol Immunopathol. 1978 Apr;9(4):499–505. doi: 10.1016/0090-1229(78)90146-0. [DOI] [PubMed] [Google Scholar]
  23. Smolen J. E., Korchak H. M., Weissmann G. The roles of extracellular and intracellular calcium in lysosomal enzyme release and superoxide anion generation by human neutrophils. Biochim Biophys Acta. 1981 Nov 5;677(3-4):512–520. doi: 10.1016/0304-4165(81)90267-1. [DOI] [PubMed] [Google Scholar]
  24. Smolen J. E., Weissmann G. The effect of various stimuli and calcium antagonists on the fluorescence response of chlorotetracycline-loaded human neutrophils. Biochim Biophys Acta. 1982 Apr 29;720(2):172–180. doi: 10.1016/0167-4889(82)90009-x. [DOI] [PubMed] [Google Scholar]
  25. Tritsch G. L., Niswander P. W. Adenosine deaminase activity and superoxide formation during phagocytosis and membrane perturbation of macrophages. Immunol Commun. 1981;10(1):1–8. doi: 10.3109/08820138109050681. [DOI] [PubMed] [Google Scholar]
  26. Tritsch G. L., Niswander P. W. Positive correlation between superoxide release and intracellular adenosine deaminase activity during macrophage membrane perturbation regardless of nature or magnitude of stimulus. Mol Cell Biochem. 1982 Nov 12;49(1):49–51. doi: 10.1007/BF00230995. [DOI] [PubMed] [Google Scholar]
  27. Wolberg G., Zimmerman T. P., Hiemstra K., Winston M., Chu L. C. Adenosine inhibition of lymphocyte-mediated cytolysis: possible role of cyclic adenosine monophosphate. Science. 1975 Mar 14;187(4180):957–959. doi: 10.1126/science.167434. [DOI] [PubMed] [Google Scholar]
  28. Zurier R. B., Hoffstein S., Weissmann G. Mechanisms of lysosomal enzyme release from human leukocytes. I. Effect of cyclic nucleotides and colchicine. J Cell Biol. 1973 Jul;58(1):27–41. doi: 10.1083/jcb.58.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. van Calker D., Müller M., Hamprecht B. Adenosine inhibits the accumulation of cyclic AMP in cultured brain cells. Nature. 1978 Dec 21;276(5690):839–841. doi: 10.1038/276839a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES