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Nitric oxide and the immune response

Abstract

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.

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Figure 1: NO pathways and antimicrobial activity.

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References

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

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

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  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. 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. 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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

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Acknowledgements

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.

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Bogdan, C. Nitric oxide and the immune response. Nat Immunol 2, 907–916 (2001). https://doi.org/10.1038/ni1001-907

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