Review Article | Published:

Nitric oxide and the immune response


During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low–molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Nathan, C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051–3064 (1992).

  2. 2

    MacMicking, J., Xie, Q.-W. & Nathan, C. Nitric oxide and macrophage function. Ann. Rev. Immunol. 15, 323–350 (1997).

  3. 3

    Stuehr, D. Mammalian nitric oxide synthases. Biochim. Biophys. Acta 1411, 217–230 (1999).

  4. 4

    Gaston, B. & Stamler, J. S. Biochemistry of nitric oxide. in Nitric Oxide and Infection (ed. Fang, F.C.) 37–55 (Kluwer/Plenum, New York, 1999).

  5. 5

    Henson, S. E., Nichols, T. C., Holers, V. M. & Karp, D. R. The ectoenzyme γ-glutamyl transpeptidase regulates antiproliferative effects of S-nitrosoglutathione on human T and B lymphocytes. J. Immunol. 163, 1845–1852 (1999).

  6. 6

    Wu, G. & Morris, S. M. Arginine metabolism: nitric oxide and beyond. Biochem. J. 336, 1–17 (1998).

  7. 7

    Eiserich, J. P. et al. Formation of nitric oxide–derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391, 393–397 (1998).

  8. 8

    MacPherson, J. C. et al. Eosinophils are a major source of nitric oxide–derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J. Immunol. 166, 5763–5772 (2001).

  9. 9

    Marshall, H. E., Merchant, K. & Stamler, J. S. Nitrosation and oxidation in the regulation of gene expression. FASEB J. 14, 1889–1900 (2000).

  10. 10

    Bogdan, C. Nitric oxide and the regulation of gene expression. Trends Cell Biol. 11, 66–75 (2001).

  11. 11

    Weinberg, J. B. Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review. Mol. Med. 4, 557–591 (1998).

  12. 12

    Kröncke, K.-D., Fehsel, K. & Kolb-Bachofen, V. Inducible nitric oxide synthase in human diseases. Clin. Exp. Immunol. 113, 147–156 (1998).

  13. 13

    Kolb, H. & Kolb-Bachofen, V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator. Immunol. Today 19, 556–561 (1998).

  14. 14

    DeGroote, M. A. & Fang, F. C. Antimicrobial properties of nitric oxide. in Nitric oxide and infection (ed. Fang, F.C.) 231–261 (Kluwer Academic/Plenum Publishers, New York, 1999).

  15. 15

    Brüne, B., von Knethen, A. & Sandau, K. B. Nitric oxide (NO): an effector of apoptosis. Cell Death Differ. 6, 969–975 (1999).

  16. 16

    Nathan, C. & Shiloh, M. U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. USA 97, 8841–8848 (2000).

  17. 17

    Bogdan, C. The function of nitric oxide in the immune system. in Handbook of Experimental Pharmacology. Volume: Nitric Oxide (ed. Mayer, B.) 443–492 (Springer, Heidelberg, 2000).

  18. 18

    Taylor-Robinson, A. W. et al. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur. J. Immunol. 24, 980–984 (1994).

  19. 19

    Thüring, H., Stenger, S., Gmehling, D., Röllinghoff, M. & Bogdan, C. Lack of inducible nitric oxide synthase activity in T cell clones and T lymphocytes from naïve and Leishmania major –infected mice. Eur. J. Immunol. 25, 3229–3234 (1995).

  20. 20

    Bauer, H. et al. Nitric oxide inhibits the secretion of T-helper 1– and T-helper 2–associated cytokines in activated human T cells. Immunology 90, 205–211 (1997).

  21. 21

    Jimenez, J. L., Gonzalez-Nicolas, J., Alvarez, S., Fresno, M. & Munoz-Fernandez, M. A. Regulation of human immunodeficiency virus type 1 replication in human T lymphocytes by nitric oxide. J. Virol. 75, 4655–4663 (2001).

  22. 22

    Reiling, N. et al. Nitric oxide synthase: expression of the endothelial, Ca2+/calmodulin-dependent isoform in human B and T lymphocytes. Eur. J. Immunol. 26, 511–516 (1996).

  23. 23

    Cruz, M. T., Carmo, A., Carvalho, A. P. & Lopes, M. C. Calcium-dependent nitric oxide synthase activity in rat thymocytes. Biochem. Biophys. Res. Commun. 248, 98–103 (1998).

  24. 24

    Williams, M. S., Noguchi, S., Henkart, P. S. & Osawa, Y. Nitric oxide synthase plays a signalling role in TCR-triggered apoptotic death. J. Immunol. 161, 6526–6531 (1998).

  25. 25

    Rodriguez-Pascual, F. et al. Complex contribution of the 3′-untranslated region to the expressional regulation of the human inducible nitric oxide synthase gene. Involvement of the RNA-binding protein HuR. J. Biol. Chem. 275, 26040–26049 (2000).

  26. 26

    Carpenter, L., Cordery, D. & Biden, T. J. Protein kinase Cd activation by interleukin-1β stabilizes inducible nitric oxide synthase mRNA in pancreatic β-cells. J. Biol. Chem. 276, 5368–5374 (2001).

  27. 27

    MacMicking, J. D. et al. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. USA 94, 5243–5248 (1997).

  28. 28

    Kleinert, H. et al. Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-κB-signaling pathways. Br. J. Pharmacol. 125, 193–201 (1998).

  29. 29

    Dlaska, M. & Weiss, G. Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J. Immunol. 162, 6171–6177 (1999).

  30. 30

    Pellacani, A. et al. Down-regulation of high mobility group-I(Y) protein contributes to the inhibition of nitric oxide synthase 2 by transforming growth factor-β1. J. Biol. Chem. 276, 1653–1659 (2001).

  31. 31

    Ganster, R.W., Taylor, B.S., Shao, L. & Geller, D.A. Complex regulation of human iNOS gene transcription by Stat1 and NF-κB. Proc. Natl. Acad. Sci. USA 98, 8638–8643 (2001).

  32. 32

    Karaghiosoff, M. et al. Partial impairment of cytokine responses in tyk2-deficient mice. Immunity 13, 549–560 (2000).

  33. 33

    Chakravortty, D. et al. The inhibitory action of sodium arsenite on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells: a role of Raf-1 in lipopolysaccharide signaling. J. Immunol. 166, 2011–2017 (2001).

  34. 34

    Chan, E. D. et al. Induction of inducible nitric oxide synthase–NO by lipoarabinomannan of Mycobacterium tuberculosis is mediated by the MEK1-ERK, MKK7-JNK and NF-κB signaling pathways. Infect. Immun. 69, 2001–2010 (2001).

  35. 35

    Kristof, A. S., Marks-Konczalik, J. & Moss, J. Mitogen-activated protein kinases mediate activator protein-1–dependent human inducible nitric oxide synthase promotor activation. J. Biol. Chem. 276, 8445–8452 (2001).

  36. 36

    Umansky, V. et al. Co-stimulatory effect of nitric oxide on endothelial NF-κB implies a physiological self-amplifying mechanism. Eur. J. Immunol. 28, 2276–2282 (1998).

  37. 37

    Connelly, L., Palacios-Callender, M., Ameixa, C., Moncada, S. & Hobbs, A. J. Biphasic regulation of NF-κB activity underlies the pro- and anti-inflammatory actions of nitric oxide. J. Immunol. 166, 3873–3881 (2001).

  38. 38

    Förstermann, U., Boissel, J. P. & Kleinert, H. Expressional control of the “constitutive” isoforms of nitric oxide synthase (NOSI and NOSIII). FASEB. J. 12, 773–790 (1998).

  39. 39

    Noguchi, S. et al. Guanabenz-mediated inactivation and enhanced proteolytic degradation of neuronal nitric oxide synthase. J. Biol. Chem. 275, 2376–2380 (2000).

  40. 40

    Felley-Bosco, E., Bender, F. C., Courjault-Gautier, F., Bron, C. & Quest, A. F. G. Caveolin-1 downregulates inducible nitric oxide synthase via the proteasome pathway in human colon carcinoma cells. Proc. Natl. Acad. Sci. USA 97, 14334–14339 (2000).

  41. 41

    Musial, A. & Eissa, N. T. Inducible nitric oxide synthase is regulated by the proteasome degradation pathway. J. Biol. Chem. 276, 24268–24273 (2001).

  42. 42

    Tochio, H., Ohki, S., Zhang, Q., Li, M. & Zhang, M. Solution structure of a protein inhibitor of neuronal nitric oxide synthase. Nature Structural Biol. 5, 965–969 (1998).

  43. 43

    Ratovitski, E. A. et al. An inducible nitric oxide synthase (NOS)–associated protein inhibits NOS dimerization and activity. J. Biol. Chem. 274, 30250–30257 (1999).

  44. 44

    Bucci, M. et al. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nature Med. 6, 1362–1367 (2000).

  45. 45

    Cao, S. et al. Direct interaction between endothelial nitric oxide synthase and dynamin-2. J. Biol. Chem. 276, 14249–14256 (2001).

  46. 46

    Pritchard, K. A. et al. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric oxide synthase. J. Biol. Chem. 276, 17621–17624 (2001).

  47. 47

    Nuszkowski, A. et al. Hypochlorite-modified low density lipoprotein inhibits nitric oxide synthesis in endothelial cells via an intracellular dislocalization of endothelial nitric oxide synthase. J. Biol. Chem. 276, 14212–14221 (2001).

  48. 48

    Chang, C., Liao, J. C. & Kuo, L. Arginase modulates nitric oxide production in activated macrophages. Am. J. Physiol. 274, H342–348 (1998).

  49. 49

    Closs, E. I., Scheld, J.-S., Sharafi, M. & Förstermann, U. Substrate supply for nitric oxide synthase in macrophages and endothelial cells: role of cationic amino acid transporters. Mol. Pharmacol. 57, 68–74 (2000).

  50. 50

    Nicholson, B., Manner, C. K., Kleeman, J. & MacLeod, C. L. Sustained nitric oxide production in macrophages requires the arginine transporter CAT2. J. Biol. Chem. 276, 15881–15885 (2001).

  51. 51

    Munder, M. et al. Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J. Immunol. 163, 3771–3777 (1999).

  52. 52

    Gotoh, T. & Mori, M. Arginase II downregulates nitric oxide (NO) production and prevents NO-mediated apoptosis in murine macrophage-derived RAW264.7 cells. J. Cell Biol. 144, 427–434 (1999).

  53. 53

    Rutschman, R. et al. Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).

  54. 54

    Coccia, E. M., Stellacci, E., Marziali, G., Weiss, G. & Battistini, A. IFN-γ and IL-4 differently regulate inducible NO synthase gene expression through IRF-1 modulation. Int. Immunol. 12, 977–985 (2000).

  55. 55

    Fligger, J., Blum, J. & Jungi, T. W. Induction of intracellular arginase activity does not diminish the capacity of macrophages to produce nitric oxide in vitro. Immunobiol. 200, 169–186 (1999).

  56. 56

    Hattori, Y., Campbell, E. B. & Gross, S. S. Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. J. Biol. Chem. 269, 9405–9408 (1994).

  57. 57

    Nüssler, A. K., Billiar, T. R., Liu, Z.-Z. & Morris, S. M. Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. J. Biol. Chem. 269, 1257–1261 (1994).

  58. 58

    Nagasaki, A. et al. Coinduction of nitric oxide synthase, argininosuccinate synthetase, and argininosuccinate lyase in lipopolysaccharide-treated rats. J. Biol. Chem. 271, 2658–2662 (1996).

  59. 59

    Flam, B.R., Hartmann, P.J., Harrell-Booth, M., Solomonson, L.P. & Eichler, D.C. Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase and lyase, with endothelial nitric oxide synthase. Nitric Oxide 5, 187–197 (2001).

  60. 60

    Werner-Felmayer, G., Golderer, G. & Werner, E. R. Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. Curr. Drug Metabol. (in the press, 2001).

  61. 61

    Michel, T. & Feron, O. Nitric oxide synthases: which, where, how, and why? J. Clin. Invest. 100, 2146–2152 (1997).

  62. 62

    Morales-Ruiz, M. et al. Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3–kinase pathway in endothelial cells. J. Biol. Chem. 276, 19672–19677 (2001).

  63. 63

    Fritzsche, G., Larcher, C., Schennach, H. & Weiss, G. Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection. J. Infect. Dis. 183, 1388–1394 (2001).

  64. 64

    Frucht, D. M. et al. Interferon-γ production by antigen presenting cells: mechanisms emerge. Trends Immunol. (in the press, 2001).

  65. 65

    Mori, N. et al. Expression of human inducible nitric oxide synthase gene in T-cell lines infected with human T cell leukemia virus type I and primary adult T-cell leukemia cells. Blood 94, 2862–2870 (1999).

  66. 66

    Gao, J.J. et al. Bacterial DNA and LPS act in synergy in inducing nitric oxide production in RAW 264.7 macrophages. J. Immunol. 163, 4095–4099 (1999).

  67. 67

    Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).

  68. 68

    Cherayil, B. J., McCormick, B. A. & Bosley, J. Salmonella enterica serovar typhimurium–dependent regulation of inducible nitric oxide synthase expression in macrophages by invasins SipB, SipC, SipD and effector SopE2. Infect. Immun. 68, 5567–5574 (2000).

  69. 69

    Shoda, L. K. M. et al. DNA from protozoan parasites Babesia bovis, Trypanosoma cruzi, T. brucei is mitogenic for B lymphocytes and stimulates macrophage expression of interleukin-12, tumor necrosis factor-α and nitric oxide. Infect. Immun. 69, 2162–2171 (2001).

  70. 70

    Thoma-Uszynski, S. et al. Induction of direct antimicrobial activity through mammalian Toll-like receptors. Science 291, 1544–1547 (2001).

  71. 71

    Freire-de-Lima, C. G. et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403, 199–203 (2000).

  72. 72

    Trimmer, B. A. et al. Nitric oxide and the control of firefly flashing. Science 292, 2486–2488 (2001).

  73. 73

    Pfeilschifter, J., Eberhardt, W. & Beck, K.-F. Regulation of gene expression by nitric oxide. Pflügers Archiv Eur. J. Physiol. 442, 479–486 (2001).

  74. 74

    Zamora, R. et al. A DNA microarray study of nitric oxide–induced genes in mouse hepatocytes: implications for hepatic heme oxygenase-1 expression in ischemia/reperfusion. submitted for publication (2001).

  75. 75

    Ehrt, S. et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. (in the press, 2001).

  76. 76

    Grisham, M. B., Granger, D. N. & Lefer, D. J. Modulation of leukocyte–endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemic heart disease. Free Rad. Biol. Med. 25, 404–433 (1998).

  77. 77

    Spiecker, M., Darius, H., Kaboth, K., Hübner, F. & Liao, J. K. Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. J. Leukoc. Biol. 63, 732–739 (1998).

  78. 78

    Lefer, D. J. et al. Leukocyte–endothelial cell interactions in nitric oxide synthase–deficient mice. Am. J. Physiol. 276, H1943–H1950 (1999).

  79. 79

    Banick, P. D., Chen, Q., Xu, Y. A. & Thom, S. R. Nitric oxide inhibits neutrophil β2 integrin function by inhibiting membrane-associated cyclic cGMP synthesis. J. Cell. Physiol. 172, 12–24 (1997).

  80. 80

    Hickey, M. J. et al. Inducible nitric oxide synthase–deficient mice have enhanced leukocyte–endothelium interactions in endotoxemia. FASEB J. 11, 955–964 (1997).

  81. 81

    Mach, F. et al. Differential expression of three T lymphocyte–activating CXC chemokines by human atheroma-associated cells. J. Clin. Invest. 104, 1041–1050 (1999).

  82. 82

    Trifilieff, A. et al. Inducible nitric oxide synthase inhibitors suppress airway inflammation in mice through down-regulation of chemokine expression. J. Immunol. 165, 1526–1533 (2000).

  83. 83

    Sato, E., Simpson, K. L., Grisham, M. B., Koyama, S. & Robbins, R. A. Reactive nitrogen and oxygen species attenuate interleukin-8-induced neutrophil chemotactic activity in vitro. J. Biol. Chem. 275, 10826–10830 (2000).

  84. 84

    Cherla, R. P. & Ganu, R. K. Stromal cell–derived factor 1α–induced chemotaxis in T cells is mediated by itric oxide signaling pathways. J. Immunol. 166, 3067–3074 (2001).

  85. 85

    Tai, X.-G. et al. Expression of an inducible type of nitric oxide (NO) synthase in the thymus and involvement of NO in deletion of TCR-stimulated double-positive thymocytes. J. Immunol. 158, 4696–4703 (1997).

  86. 86

    Aiello, S. et al. Thymic dendritic cells express inducible nitric oxide synthase and generate nitric oxide in response to self- and alloantigens. J. Immunol. 164, 4649–4658 (2000).

  87. 87

    Moulian, N., Truffault, F., Gaudry-Talarmain, Y. M., Serraf, A. & Berrih-Aknin, S. In vivo and in vitro apoptosis of human thymocytes are associated with nitrotyrosine formation. Blood 97, 3521–3530 (2001).

  88. 88

    Fehsel, K. et al. Nitric oxide induces apoptosis in mouse thymocytes. J. Immunol. 155, 2858–2865 (1995).

  89. 89

    Brito, C. et al. Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxinitrite-driven apoptotic death. J. Immunol. 162, 3356–3366 (1999).

  90. 90

    Kwak, J.-Y. et al. Cytokines secreted by lymphokine-activated killer cells induce endogenous nitric oxide synthesis and apoptosis in DLD-1 colon cancer cells. Cell. Immunol. 203, 84–94 (2000).

  91. 91

    DiNapoli, M. R., Calderon, C. & Lopez, D. The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduced expression of the inducible nitric oxide synthase. J. Exp. Med. 183, 1323–1329 (1996).

  92. 92

    Hung, K. et al. The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188, 2357–2368 (1998).

  93. 93

    Xu, W., Liu, L., Smith, G. C. M. & Charles, I. G. Nitric oxide upregulates expression of DNA-PKcs to protect cells from DNA-damaging anti-tumor agents. Nature Cell Biol. 2, 339–345 (2000).

  94. 94

    Luckhart, S., Vodovotz, Y., Cui, L. & Rosenberg, R. The mosquito Anopheles stephensi limits malaria parasite development with inducible nitric oxide synthesis. Proc. Natl. Acad. Sci. USA 95, 5700–5705 (1998).

  95. 95

    Ribeiro, J. M. C., Hazzard, J. M. H., Nussenzweig, R. H., Champagne, D. E. & Walker, F. A. Reversible binding of nitric oxide by a salivary heme protein from a bloodsucking insect. Science 260, 539–541 (1993).

  96. 96

    Hall, L. R. & Titus, R. G. Sandfly vector saliva selectively modulates macrophage functions that inhibit killing of Leishmania major and nitric oxide production. J. Immunol. 155, 3501–3506 (1995).

  97. 97

    Kuthejlova, M., Kopecky, J., Stepanova, G. & Macela, A. Tick salivary gland extract inhibits the killing of Borrelia afzelii spirochetes by mouse macrophages. Infect. Immun. 69, 575–578 (2001).

  98. 98

    Hesse, M., Cheever, A. W., Jankovic, D. & Wynn, T. A. NOS-2 mediates the protective anti-inflammatory and anti-fibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease. Am. J. Pathol. 157, 945–955 (2000).

  99. 99

    Bogdan, C., Röllinghoff, M. & Diefenbach, A. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr. Opin. Immunol. 12, 64–76 (2000).

  100. 100

    Chandrasekar, B., Melby, P. C., Troyer, D. A. & Freeman, G. L. Differential regulation of nitric oxide synthase isoforms in experimental acute Chagasic cardiomyopathy. Clin. Exp. Immunol. 121, 112–119 (2000).

  101. 101

    Iwase, K. et al. Induction of endothelial nitric oxide synthase in rat brain astrocytes by systemic lipopolysaccharide treatment. J. Biol. Chem. 275, 11929–11933 (2000).

  102. 102

    van der Heyde, H. C., Gu, Y., Zhang, Q., Sun, G. & Grisham, M. B. Nitric oxide is neither necessary nor sufficient for resolution of Plasmodium chabaudi malaria in mice. J. Immunol. 165, 3317–3323 (2000).

  103. 103

    Winkler, F., Koedel, U., Kastenbauer, S. & Pfister, H. W. Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood–brain barrier breakdown. J. Infect. Dis. 183, 1749–1759 (2001).

  104. 104

    Vazquez-Torres, A., Jones-Carson, J., Mastroeni, P., Ischiropoulos, H. & Fang, F. C. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. J. Exp. Med. 192, 227–236 (2000).

  105. 105

    Pfeiffer, S., Lass, A., Schmidt, K. & Mayer, B. Protein tyrosine nitration in cytokine-activated murine macrophages involvement of a peroxidase/nitrite pathway rather than peroxinitrite. J. Biol. Chem. 276: 34051–34058 (in the press; published online June 25, 2001).

  106. 106

    St John, G. et al. Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates. Proc. Natl. Acad. Sci. USA 98, 9901–9906 (2001).

  107. 107

    Bryk, R., Griffin, P. & Nathan, C. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407, 211–215 (2000).

  108. 108

    Olds, G. R., Ellner, J. J., Kearse, L. A., Kazura, J. W. & Mahmoud, A. A. F. Role of arginase in killing of schistosomula of Schistosoma mansoni. J. Exp. Med. 151, 1557–1562 (1980).

  109. 109

    Eckmann, L. et al. Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia. J. Immunol. 164, 1478–1487 (2000).

  110. 110

    Piacenza, L., Peluffo, G. & Radi, R. l-arginine–dependent suppression of apoptosis in Trypanosoma cruzi: contribution of the nitric oxide and polyamine pathways. Proc. Natl. Acad. Sci. USA 98, 7301–7306 (2001).

  111. 111

    Iniesta, V., Gomez-Nieto, L. C. & Corraliza, I. The inhibition of arginase by Nω-hydroxy-l-arginine controls the growth of Leishmania inside macrophages. J. Exp. Med. 193, 777–783 (2001).

  112. 112

    Gobert, A. P. et al. l-arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis. Infect. Immun. 68, 4653–4657 (2000).

  113. 113

    Diefenbach, A., Schindler, H., Röllinghoff, M., Yokoyama, W. & Bogdan, C. Requirement for type 2 NO-synthase for IL-12 responsiveness in innate immunity. Science 284, 951–955 (1999).

  114. 114

    Andonegui, G. et al. Effect of nitric oxide donors on oxygen-dependent cytotoxic responses by neutrophils. J. Immunol. 162, 2922–2930 (1999).

  115. 115

    Lee, C., Miura, K., Liu, X. & Zweier, J. L. Biphasic regulation of leukocyte superoxide generation by nitric oxide and peroxinitrite. J. Biol. Chem. 275, 38965–38972 (2000).

  116. 116

    Dalton, D. K., Haynes, L., Chu, C.-Q., Swain, S. L. & Wittmer, S. Interferon-γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J. Exp. Med. 192, 117–122 (2000).

  117. 117

    Rai, R. M. et al. Impaired liver regeneration in inducible nitric oxide synthase–deficient mice. Proc. Natl. Acad. Sci. USA 95, 13829–13834 (1998).

  118. 118

    Li, J., Bombeck, C. A., Yang, S., Kim, Y.-M. & Billiar, T. R. Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J. Biol. Chem. 274, 17325–17333 (1999).

  119. 119

    Efron, D. T., Most, D. & Barbul, A. Role of nitric oxide in wound healing. Curr. Opin. Clin. Nutr. Metab. Care 3, 197–204 (2000).

  120. 120

    Murray, H. W. & Nathan, C. F. Macrophage microbicidal mechanisms in vivo: reactive nitrogen vs. oxygen intermediates in the killing of intracellular visceral Leishmania donovani. J. Exp. Med. 189, 741–746 (1999).

  121. 121

    Mastroni, P. et al. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects of microbial proliferation and host survival in vivo. J. Exp. Med. 192, 237–247 (2000).

  122. 122

    Cooper, A. M., Pearl, J. E., Brooks, J. V., Ehlers, S. & Orme, I. M. Expression of nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect. Immun. 68, 6879–6882 (2000).

  123. 123

    Saeftel, M., Fleischer, B. & Hoerauf, A. Stage-dependent role of nitric oxide in control of Trypanosoma cruzi infection. Infect. Immun. 69, 2252–2259 (2001).

  124. 124

    Wilhelm, P. et al. Rapidly fatal leishmaniasis in resistant C57BL/6 mice lacking tumor necrosis factor. J. Immunol. 166, 4012–4019 (2001).

  125. 125

    Scanga, C. A. et al. Depletion of CD4+ T cells causes reactivation of murine persistent tuberculosis despite continued expression of IFN-γ and nitric oxide synthase 2. J. Exp. Med. 192, 347–358 (2000).

  126. 126

    Nabeshima, S. et al. T cell hyporesponsiveness induced by activated macrophages through nitric oxide production in mice infected with Mycobacterium tuberculosis. Infect. Immun. 67, 3221–3226 (1999).

  127. 127

    Adamson, D. C. et al. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274, 1917–1921 (1996).

  128. 128

    Khanolkar-Young, S., Snowdon, D. & Lockwood, D. N. J. Immunocytochemical localization of inducible nitric oxide synthase and transforming growth factor-β (TGF-β) in leprosy lesions. Clin. Exp. Immunol. 113, 438–442 (1998).

  129. 129

    Perkins, D. J. et al. Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy Gabonese children with prior mild or severe malaria. Infect. Immun. 67, 4977–4981 (1999).

  130. 130

    Chiwakata, C. B., Hemmer, C. J. & Dietrich, M. High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria. Infect. Immun. 68, 394–399 (2000).

  131. 131

    Weiss, G. et al. Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria. J. Infect. Dis. 177, 1064–1068 (1998).

  132. 132

    Maneerat, Y. et al. Inducible nitric oxide synthase expression is increased in the brain in fatal cerebral malaria. Histopathology 37, 269–277 (2000).

  133. 133

    Lee, P. C., Shears, L. L. & Billiar, T. R. Role of inducible nitric oxide synthase in transplant atherosclerosis. Clin. Exp. Pharmacol. Physiol. 26, 1013–1015 (1999).

  134. 134

    Vos, I. H. C. et al. Inhibition of inducible nitric oxide synthase improves graft function and reduces tubulointerstitial injury in renal allograft rejection. Eur. J. Pharmacol. 391, 31–38 (2000).

  135. 135

    Bobe, P. et al. Nitric oxide mediation of active immunosuppression associated with graft-versus-host reaction. Blood 94, 1028–1037 (1999).

  136. 136

    Bogdan, C. The multiplex function of nitric oxide in (auto)immunity. J. Exp. Med. 187, 1361–1365 (1998).

  137. 137

    Gilkeson, G. S. et al. Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2. J. Exp. Med. 186, 365–373 (1997).

  138. 138

    McCartney-Francis, N. L., Song, X.-Y., Mizel, D. E. & Wahl, S. M. Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J. Immunol. 166, 2734–2740 (2001).

  139. 139

    Tarrant, T. K. et al. Interleukin-12 protects from a Th1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving IFN-γ, nitric oxide and apoptosis. J. Exp. Med. 189, 219–230 (1999).

  140. 140

    Kahn, D. A., Archer, D. C., Gold, D. P. & Kelly, C. J. Adjuvant immunotherapy is dependent on inducible nitric oxide synthase. J. Exp. Med. 193, 1261–1267 (2001).

  141. 141

    Shi, F.-D. et al. Control of the autoimmune response by type 2 nitric oxide synthase. J. Immunol. 167, 3000–3006 (2001).

  142. 142

    Paul-Clark, M. J., Gilroy, D. W., Willis, D., Willoughby, D. A. & Tomlinson, A. Nitric oxide synthase inhibitors have opposite effects on acute inflammation depending on their route of administration. J. Immunol. 166, 1169–1177 (2001).

  143. 143

    Cauwels, A. et al. Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase. Immunity 13, 223–231 (2000).

  144. 144

    Xie, K., Dong, Z. & Fidler, I. J. Activation of nitric oxide gene for inhibition of cancer metastasis. J. Leukoc. Biol. 797, 797–803 (1996).

  145. 145

    Pervin, S., Singh, R. & Chaudhuri, G. Nitric oxide–induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): potential role of cyclin D1. Proc. Natl. Acad. Sci. USA 98, 3583–3588 (2001).

  146. 146

    Allione, A. et al. Nitric oxide suppresses human T lymphocyte proliferation through IFN-gamma–dependent and IFN-gamma–independent induction of apoptosis. J. Immunol. 163, 4182–4191 (1999).

  147. 147

    Angulo, I. et al. Nitric oxide producing CD11b+ Ly-6G(Gr-1)+CD31(ER-MP12)+ cells in the spleen of cyclophosphamide-treated mice: implications for T cell responses in immunosuppressed mice. Blood 95, 212–220 (2000).

  148. 148

    Berendji, D., et al. Zinc finger transcription factor as molecular target for nitric oxide–mediated immunosuppression: inhibition of IL-2 gene expression in lymphocytes. Mol. Med. 5 (11):721–730 (1999).

  149. 149

    Wang, S., Yan, L., Wesley, R. A. & Danner, R. L. A Sp1 binding site of the tumor necrosis factor α promotor functions as a nitric oxide response element. J. Biol. Chem. 274, 33190–33193 (1999).

  150. 150

    Vodovotz, Y. et al. Regulation of transforming growth factor β1 by nitric oxide. Cancer Res. 59, 2142–2149 (1999).

  151. 151

    Zhang, Z. et al. Activation of tumor necrosis factor-α–converting enzyme–mediated ectodomain shedding by nitric oxide. J. Biol. Chem. 275, 15839–15844 (2000).

  152. 152

    Uma, S., Yun, B.-G. & Matts, R. L. The heme-regulated eukaryotic initiation factor 2α kinase. A potential regulatory target for control of protein synthesis by diffusible gases. J. Biol. Chem. 276, 14875–14883 (2001).

  153. 153

    Schindler, H. & Bogdan, C. NO as a signaling molecule: effects on kinases. Internat. Immunopharmacol. 1, 1443–1455 (2001).

  154. 154

    Niedbala, W., Wei, X.-Q., Piedrafita, D., Xu, D. & Liew, F. Y. Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur. J. Immunol. 29, 2498–2505 (1999).

  155. 155

    Miles, P. R., Bowman, L., Rengasamy, A. & Huffman, L. Constitutive nitric oxide production by rat alveolar macrophages. Am. J. Physiol. 274, L360–L368 (1998).

  156. 156

    Roman, V. et al. Characterization of a constitutive type III nitric oxide synthase in human U937 monocytic cells: stimulation by soluble CD23. Immunology 91, 643–648 (1997).

  157. 157

    Blank, C., Bogdan, C., Bauer, C., Erb, K. & Moll, H. Murine epidermal Langerhans cells do not express inducible nitric oxide synthase. Eur. J. Immunol. 26, 792–796 (1996).

  158. 158

    Qureshi, A. A. et al. Langerhans cells express inducible nitric oxide synthase and produce nitric oxide. J. Invest. Dermatol. 107, 815–821 (1996).

  159. 159

    Ross, R. et al. Involvement of NO in contact hypersensitivity. Int. Immunol. 10, 61–69 (1998).

  160. 160

    Lu, L. et al. Induction of nitric oxide synthase in mouse dendritic cells by IFN-γ, endotoxin, and interaction with allogeneic T cells. Nitric oxide production is associated with dendritic cell apoptosis. J. Immunol. 157, 3577–3586 (1996).

  161. 161

    Bodnar, K. A., Serbina, N. V. & Flynn, J. L. Fate of Mycobacterium tuberculosis within murine dendritic cells. Infect. Immun. 69, 800–809 (2001).

  162. 162

    Cruz, M. T., Duarte, C. B., Goncalo, M., Carvalho, A. P. & Lopes, M. C. LPS induction of IκB-α degradation and iNOS expression in a skin dendritic cell line is prevented by the Janus kinase 2 inhibitor, tyrphostin B42. Nitric Oxide 5, 53–61 (2001).

  163. 163

    Burnett, T. G. & Hunt, J. S. Nitric oxide synthase–2 and expression of perforin in uterine NK cells. J. Immunol. 164, 5245–5250 (2000).

  164. 164

    Cifone, M. G. et al. Interleukin-2 activated rat natural killer cells express inducible nitric oxide synthase that contributes to cytotoxic function and interferon-γ production. Blood 93, 3876–3884 (1999).

  165. 165

    Salvucci, O., Kolb, J. P., Dugas, B., Dugas, N. & Chouaib, S. The induction of nitric oxide by interleukin-12 and tumor necrosis factor-α in human natural killer cells: relationship with the regulation of lytic activity. Blood 92, 2093–2102 (1998).

  166. 166

    Furuke, K. et al. Human NK cells express endothelial nitric oxide synthase, and nitric oxide protects them from activation-induced cell death by regulating expression of TNF-α. J. Immunol. 163, 1473–1480 (1999).

  167. 167

    Mannick, J. B. et al. Fas-induced caspase denitrosylation. Science 284, 651–654 (1999).

  168. 168

    Sciorati, C. et al. Autocrine nitric oxide modulates CD95-induced apoptosis in γδ T lymphocytes. J. Biol. Chem. 272, 23211–23215 (1997).

  169. 169

    Zhao, H. et al. B-cell chronic lymphocytic leukemia cells express a functional inducible nitric oxide synthase displaying anti-apoptotic activity. Blood 92, 1031–1043 (1998).

  170. 170

    Bartholdy, C., Nansen, A., Christensen, J. E., Marker, O. & Thomsen, A. R. Inducible nitric oxide synthase plays a minimal role in LCMV-induced, T cell–mediated protective immunity and immunopathology. J. Gen. Virol. 80, 2997–3005 (1999).

  171. 171

    Noda, S. et al. Role of nitric oxide synthase type 2 in acute infection with cytomegalovirus. J. Immunol. 166, 3533–3541 (2001).

  172. 172

    Wu, G. F., Pewe, L. & Perlman, S. Coronavirus-induced demyelination occurs in the absence of inducible nitric oxide synthase. J. Virol. 74, 7683–7686 (2000).

  173. 173

    Brown, C. & Reiner, S. L. Development of Lyme arthritis in mice deficient in inducible nitric oxide synthase. J. Infect. Dis. 179, 1573–1576 (1999).

  174. 174

    Nathan, C. Inducible nitric oxide synthase: what difference does it make? J. Clin. Invest. 100, 2417–2423 (1997).

  175. 175

    Adams, L. B., Job, C. K. & Krahenbuhl, J. L. Role of inducible nitric oxide synthase in resistance to Mycobacterium leprae in mice. Infect. Immun. 68, 5462–5465 (2000).

  176. 176

    Smith, A. L. & Hayday, A. C. Genetic dissection of primary and secondary responses to a widespread natural pathogen of the gut, Eimeria vermiformis. Infect. Immun. 68, 6273–6280 (2000).

  177. 177

    Hertz, C. J. & Mansfield, J. M. IFN-γ–dependent nitric oxide production is not linked to resistance in experimental African trypanosomiasis. Cell. Immunol. 192, 24–32 (1999).

  178. 178

    Flodstrom, M. et al. A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. Virology 281, 205–215 (2001).

  179. 179

    Martins, G. A. et al. Fas–FasL interaction modulates nitric oxide production in Trypanosoma cruzi –infected mice. Immunology 103, 122–129 (2001).

  180. 180

    Guidotti, L. G., McClary, H., Moorhead Loudis, J. & Chisari, F. V. Nitric oxide inhibits hepatitis B virus replication in the livers of transgenic mice. J. Exp. Med. 191, 1247–1252 (2000).

  181. 181

    Banerjee, R., Anguita, J. & Fikrig, E. Granulocytic ehrlichiosis in mice deficient in phagocyte oxidase or inducible nitric oxide synthase. Infect. Immun. 68, 4361–4362 (2000).

  182. 182

    Jin, Y., Dons, L., Kristensson, K. & Rottenberg, M. E. Neural route of cerebral Listeria monocytogenes murine infection: role of immune response mechanisms in controlling bacterial neuroinvasion. Infect. Immun. 69, 1093–1100 (2001).

  183. 183

    Leitch, G. J. & He, Q. Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model. Infect. Immun. 67, 5885–5891 (1999).

  184. 184

    Seydel, K. B., Smith, S. J. & Stanley, S. L. Innate immunity to amebic liver abscess is dependent on γ interferon and nitric oxide in a murine model of disease. Infect. Immun. 68, 400–402 (2000).

  185. 185

    Millar, A. E. et al. T cell responses during Trypanosoma brucei infections in mice deficient in inducible nitric oxide synthase. Infect. Immun. 67, 3334–3338 (1999).

  186. 186

    Huang, H. et al. Expression of cardiac cytokines and inducible nitric oxide synthase (NOS2) in Trypanosoma cruzi –infected mice. J. Mol. Cell. Cardiol. 31, 75–88 (1999).

  187. 187

    Bauer, P. M. et al. Nitric oxide inhibits ornithine decarboxylase via S-nitrosylation of cysteine 360 in the active site of the enzyme. J. Biol. Chem. 276, 34458–34464 (2001).

  188. 188

    Akaike, T. et al. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J. 14, 1147–1454 (2000).

  189. 189

    Zaragoza, C. et al. Nitric oxide synthase protection against Coxsackievirus pancreatitis. J. Immunol. 163, 5497–5504

Download references


Supported by a grant from the Deutsche Forschungsgemeinschaft (SFB263, A5). I thank C. Nathan, M. Röllinghoff, U. Schleicher and Y. Vodovotz for helpful comments and sharing preprints. I apologize to all authors whose original publications I could cite only indirectly by reference to review articles because of strict space limitations.

Author information

Correspondence to Christian Bogdan.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Figure 1: NO pathways and antimicrobial activity.