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(Journal of Leukocyte Biology. 2007;81:579.)
© 2007 by Society for Leukocyte Biology

Macrophage biology and immunology: man is not a mouse

Markus Schneemann1 and Gabriele Schoeden

Department of Medicine, University Hospital of Zürich, Zürich, Switzerland

1 Correspondence: Department of Medicine, University Hospital of Zürich, Raemistrasse 100, Zürich CH-8091, Switzerland. E-mail: schneema{at}yahoo.com

Key Words: nitric oxide • species differences • NO synthase • arginase

A recent article by Shibata et al. [1] and an interview with the senior investigator Kobayashi [2], both in the October 2006 issue of Journal of Leukocyte Biology, discuss the role of macrophage-derived NO in the clearance of apoptotic cells. We were surprised that neither in the original paper nor in the accompanying interview was it discussed that these results rely entirely on data obtained in murine macrophages. It is, however, evident that there are differences in macrophage NO production and regulation among different species [3 4 ]. Several years ago, we and others [5 6 7 ] described fundamental differences between macrophages from mice and humans regarding NO synthase (NOS) activity. Murine macrophages produce large amounts of NO and L-citrulline from L-arginine via induction of the inducible form of NOS (iNOS). In parallel, murine macrophages synthesize the obligatory cofactor tetrahydrobiopterin (BH4), essential for stabilization and function of the iNOS enzyme protein [8 9 ]. Human as well as macrophages from other animal species, such as rabbits, goats, or Syrian hamsters, do not have NOS activity nor do they synthesize BH4 [7 10 11 ]. In addition, murine macrophages consume most of the L-arginine by another enzyme—arginase—and convert it into L-ornithine. This arginase is not active in human macrophages too [7 9 12 ]. A lot of research has since been done to demonstrate nitrite production in human macrophages. Recent reviews claim that human macrophages have iNOS activity, albeit induced by other stimuli rather than those inducing nitrite production in murine macrophages [13 ]. We evaluated several of these stimuli and could show that nitrite was not produced by iNOS activity in human macrophages. The nitrite measured came from other noncellular sources [14 ]. None of the articles cited as proof for iNOS activity in human macrophages provides sound biochemical data about L-arginine consumption, BH4 synthesis, and L-citrulline production [13 ]. Moreover, they do not control for nitrite generation from other nonmacrophage sources [14 ]. The only report that demonstrates nitrite production from NOS activity in human macrophage-like cells is an article by Bertholet et al. [15 ]. There, the U937 monoblastic leukemia cell line was transfected with a plasmid containing a functional iNOS gene. Nitrite production by these cells, however, totally depended on substitution of the cofactor BH4 and additional substrate [15 ]. As species differences are not confined to NOS activity and are fundamental in many aspects of immunology [3 16 17 ], we propose that the species involved should be mentioned in the title and abstract of articles dealing with common aspects of immunity.

Received November 28, 2006; revised December 4, 2006; accepted December 4, 2006.

REFERENCES

  1. Shibata, T., Nagata, K., Kobayashi, Y. (2006) A suppressive role of nitric oxide in MIP-2 production by macrophages upon coculturing with apoptotic cells J. Leukoc. Biol. 80,744-752[Abstract/Free Full Text]
  2. Kobayashi, Y. (2006) Interview with Dr. Yoshiro Kobayashi regarding pivotal advance: a suppressive role of nitric oxide in MIP-2 production by macrophages upon coculturing with apoptotic cells. Interview by Helene F. Rosenberg and Joost J. Oppenheim J. Leukoc. Biol. 80,742-743[Free Full Text]
  3. Mestas, J., Hughes, C. C. (2004) Of mice and not men: differences between mouse and human immunology J. Immunol. 172,2731-2738[Abstract/Free Full Text]
  4. Schneemann, M., Schoedon, G. (2002) Species differences in macrophage NO production are important Nat. Immunol. 3,102[Medline]
  5. Murray, H. W., Teitelbaum, R. F. (1992) L-arginine-dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes J. Infect. Dis. 165,513-517[Medline]
  6. Padgett, E. L., Pruett, S. B. (1992) Evaluation of nitrite production by human monocyte-derived macrophages Biochem. Biophys. Res. Commun. 186,775-781[CrossRef][Medline]
  7. Schneemann, M., Schoedon, G., Hofer, S., Blau, N., Guerrero, L., Schaffner, A. (1993) Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes J. Infect. Dis. 167,1358-1363[Medline]
  8. Tayeh, M. A., Marletta, M. A. (1989) Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor J. Biol. Chem. 264,19654-19658[Abstract/Free Full Text]
  9. Schoedon, G., Schneemann, M., Hofer, S., Guerrero, L., Blau, N., Schaffner, A. (1993) Regulation of the L-arginine-dependent and tetrahydrobiopterin-dependent biosynthesis of nitric oxide in murine macrophages Eur. J. Biochem. 213,833-839[Medline]
  10. Pfister, H., Remer, K. A., Brcic, M., Fatzer, R., Christen, S., Leib, S., Jungi, T. W. (2002) Inducible nitric oxide synthase and nitrotyrosine in listeric encephalitis: a cross-species study in ruminants Vet. Pathol. 39,190-199[Abstract/Free Full Text]
  11. Perez, L. E., Chandrasekar, B., Saldarriaga, O. A., Zhao, W., Arteaga, L. T., Travi, B. L., Melby, P. C. (2006) Reduced nitric oxide synthase 2 (NOS2) promoter activity in the Syrian hamster renders the animal functionally deficient in NOS2 activity and unable to control an intracellular pathogen J. Immunol. 176,5519-5528[Abstract/Free Full Text]
  12. Albina, J. E., Reichner, J. S. (2003) Oxygen and the regulation of gene expression in wounds Wound Repair Regen. 11,445-451[CrossRef][Medline]
  13. Fang, F. C. (2004) Antimicrobial reactive oxygen and nitrogen species: concepts and controversies Nat. Rev. Microbiol. 2,820-832[CrossRef][Medline]
  14. Schneemann, M., Schoedon, G., Linscheid, P., Walter, R., Blau, N., Schaffner, A. (1997) Nitrite generation in interleukin-4-treated human macrophage cultures does not involve the nitric oxide synthase pathway J. Infect. Dis. 175,130-135[Medline]
  15. Bertholet, S., Tzeng, E., Felley-Bosco, E., Mauel, J. (1999) Expression of the inducible NO synthase in human monocytic U937 cells allows high output nitric oxide production J. Leukoc. Biol. 65,50-58[Abstract]
  16. Haley, P. J. (2003) Species differences in the structure and function of the immune system Toxicology 188,49-71[CrossRef][Medline]
  17. Marr, K. J., Jones, G. J., Mody, C. H. (2006) Contemplating the murine test tube: lessons from natural killer cells and Cryptococcus neoformans FEMS Yeast Res. 6,543-557[CrossRef][Medline]

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