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.
Your institute does not have access to this article
Open Access articles citing this article.
Histidine acid phosphatase domain-containing protein from Haemonchus contortus is a stimulatory antigen for the Th1 immune response of goat PBMCs
Parasites & Vectors Open Access 06 August 2022
Biophysical evaluation of treating adipose tissue-derived stem cells using non-thermal atmospheric pressure plasma
Scientific Reports Open Access 01 July 2022
Inhaled nitric oxide: role in the pathophysiology of cardio-cerebrovascular and respiratory diseases
Intensive Care Medicine Experimental Open Access 27 June 2022
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nathan, C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051–3064 (1992).
MacMicking, J., Xie, Q.-W. & Nathan, C. Nitric oxide and macrophage function. Ann. Rev. Immunol. 15, 323–350 (1997).
Stuehr, D. Mammalian nitric oxide synthases. Biochim. Biophys. Acta 1411, 217–230 (1999).
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).
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).
Wu, G. & Morris, S. M. Arginine metabolism: nitric oxide and beyond. Biochem. J. 336, 1–17 (1998).
Eiserich, J. P. et al. Formation of nitric oxide–derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391, 393–397 (1998).
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).
Marshall, H. E., Merchant, K. & Stamler, J. S. Nitrosation and oxidation in the regulation of gene expression. FASEB J. 14, 1889–1900 (2000).
Bogdan, C. Nitric oxide and the regulation of gene expression. Trends Cell Biol. 11, 66–75 (2001).
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).
Kröncke, K.-D., Fehsel, K. & Kolb-Bachofen, V. Inducible nitric oxide synthase in human diseases. Clin. Exp. Immunol. 113, 147–156 (1998).
Kolb, H. & Kolb-Bachofen, V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator. Immunol. Today 19, 556–561 (1998).
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).
Brüne, B., von Knethen, A. & Sandau, K. B. Nitric oxide (NO): an effector of apoptosis. Cell Death Differ. 6, 969–975 (1999).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Karaghiosoff, M. et al. Partial impairment of cytokine responses in tyk2-deficient mice. Immunity 13, 549–560 (2000).
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).
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).
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).
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).
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).
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).
Noguchi, S. et al. Guanabenz-mediated inactivation and enhanced proteolytic degradation of neuronal nitric oxide synthase. J. Biol. Chem. 275, 2376–2380 (2000).
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).
Musial, A. & Eissa, N. T. Inducible nitric oxide synthase is regulated by the proteasome degradation pathway. J. Biol. Chem. 276, 24268–24273 (2001).
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).
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).
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).
Cao, S. et al. Direct interaction between endothelial nitric oxide synthase and dynamin-2. J. Biol. Chem. 276, 14249–14256 (2001).
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).
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).
Chang, C., Liao, J. C. & Kuo, L. Arginase modulates nitric oxide production in activated macrophages. Am. J. Physiol. 274, H342–348 (1998).
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).
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).
Munder, M. et al. Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J. Immunol. 163, 3771–3777 (1999).
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).
Rutschman, R. et al. Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).
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).
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).
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).
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).
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).
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).
Werner-Felmayer, G., Golderer, G. & Werner, E. R. Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. Curr. Drug Metabol. (in the press, 2001).
Michel, T. & Feron, O. Nitric oxide synthases: which, where, how, and why? J. Clin. Invest. 100, 2146–2152 (1997).
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).
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).
Frucht, D. M. et al. Interferon-γ production by antigen presenting cells: mechanisms emerge. Trends Immunol. (in the press, 2001).
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).
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).
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).
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).
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).
Thoma-Uszynski, S. et al. Induction of direct antimicrobial activity through mammalian Toll-like receptors. Science 291, 1544–1547 (2001).
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).
Trimmer, B. A. et al. Nitric oxide and the control of firefly flashing. Science 292, 2486–2488 (2001).
Pfeilschifter, J., Eberhardt, W. & Beck, K.-F. Regulation of gene expression by nitric oxide. Pflügers Archiv Eur. J. Physiol. 442, 479–486 (2001).
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).
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).
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).
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).
Lefer, D. J. et al. Leukocyte–endothelial cell interactions in nitric oxide synthase–deficient mice. Am. J. Physiol. 276, H1943–H1950 (1999).
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).
Hickey, M. J. et al. Inducible nitric oxide synthase–deficient mice have enhanced leukocyte–endothelium interactions in endotoxemia. FASEB J. 11, 955–964 (1997).
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).
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).
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).
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).
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).
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).
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).
Fehsel, K. et al. Nitric oxide induces apoptosis in mouse thymocytes. J. Immunol. 155, 2858–2865 (1995).
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).
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).
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).
Hung, K. et al. The central role of CD4+ T cells in the antitumor immune response. J. Exp. Med. 188, 2357–2368 (1998).
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).
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).
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).
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).
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).
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).
Bogdan, C., Röllinghoff, M. & Diefenbach, A. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr. Opin. Immunol. 12, 64–76 (2000).
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).
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).
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).
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).
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).
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).
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).
Bryk, R., Griffin, P. & Nathan, C. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407, 211–215 (2000).
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).
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).
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).
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).
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).
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).
Andonegui, G. et al. Effect of nitric oxide donors on oxygen-dependent cytotoxic responses by neutrophils. J. Immunol. 162, 2922–2930 (1999).
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).
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).
Rai, R. M. et al. Impaired liver regeneration in inducible nitric oxide synthase–deficient mice. Proc. Natl. Acad. Sci. USA 95, 13829–13834 (1998).
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).
Efron, D. T., Most, D. & Barbul, A. Role of nitric oxide in wound healing. Curr. Opin. Clin. Nutr. Metab. Care 3, 197–204 (2000).
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).
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).
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).
Saeftel, M., Fleischer, B. & Hoerauf, A. Stage-dependent role of nitric oxide in control of Trypanosoma cruzi infection. Infect. Immun. 69, 2252–2259 (2001).
Wilhelm, P. et al. Rapidly fatal leishmaniasis in resistant C57BL/6 mice lacking tumor necrosis factor. J. Immunol. 166, 4012–4019 (2001).
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).
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).
Adamson, D. C. et al. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274, 1917–1921 (1996).
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).
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).
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).
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).
Maneerat, Y. et al. Inducible nitric oxide synthase expression is increased in the brain in fatal cerebral malaria. Histopathology 37, 269–277 (2000).
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).
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).
Bobe, P. et al. Nitric oxide mediation of active immunosuppression associated with graft-versus-host reaction. Blood 94, 1028–1037 (1999).
Bogdan, C. The multiplex function of nitric oxide in (auto)immunity. J. Exp. Med. 187, 1361–1365 (1998).
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).
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).
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).
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).
Shi, F.-D. et al. Control of the autoimmune response by type 2 nitric oxide synthase. J. Immunol. 167, 3000–3006 (2001).
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).
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).
Xie, K., Dong, Z. & Fidler, I. J. Activation of nitric oxide gene for inhibition of cancer metastasis. J. Leukoc. Biol. 797, 797–803 (1996).
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).
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).
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).
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).
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).
Vodovotz, Y. et al. Regulation of transforming growth factor β1 by nitric oxide. Cancer Res. 59, 2142–2149 (1999).
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).
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).
Schindler, H. & Bogdan, C. NO as a signaling molecule: effects on kinases. Internat. Immunopharmacol. 1, 1443–1455 (2001).
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).
Miles, P. R., Bowman, L., Rengasamy, A. & Huffman, L. Constitutive nitric oxide production by rat alveolar macrophages. Am. J. Physiol. 274, L360–L368 (1998).
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).
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).
Qureshi, A. A. et al. Langerhans cells express inducible nitric oxide synthase and produce nitric oxide. J. Invest. Dermatol. 107, 815–821 (1996).
Ross, R. et al. Involvement of NO in contact hypersensitivity. Int. Immunol. 10, 61–69 (1998).
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).
Bodnar, K. A., Serbina, N. V. & Flynn, J. L. Fate of Mycobacterium tuberculosis within murine dendritic cells. Infect. Immun. 69, 800–809 (2001).
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).
Burnett, T. G. & Hunt, J. S. Nitric oxide synthase–2 and expression of perforin in uterine NK cells. J. Immunol. 164, 5245–5250 (2000).
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).
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).
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).
Mannick, J. B. et al. Fas-induced caspase denitrosylation. Science 284, 651–654 (1999).
Sciorati, C. et al. Autocrine nitric oxide modulates CD95-induced apoptosis in γδ T lymphocytes. J. Biol. Chem. 272, 23211–23215 (1997).
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).
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).
Noda, S. et al. Role of nitric oxide synthase type 2 in acute infection with cytomegalovirus. J. Immunol. 166, 3533–3541 (2001).
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).
Brown, C. & Reiner, S. L. Development of Lyme arthritis in mice deficient in inducible nitric oxide synthase. J. Infect. Dis. 179, 1573–1576 (1999).
Nathan, C. Inducible nitric oxide synthase: what difference does it make? J. Clin. Invest. 100, 2417–2423 (1997).
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).
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).
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).
Flodstrom, M. et al. A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. Virology 281, 205–215 (2001).
Martins, G. A. et al. Fas–FasL interaction modulates nitric oxide production in Trypanosoma cruzi –infected mice. Immunology 103, 122–129 (2001).
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).
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).
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).
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).
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).
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).
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).
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).
Akaike, T. et al. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J. 14, 1147–1454 (2000).
Zaragoza, C. et al. Nitric oxide synthase protection against Coxsackievirus pancreatitis. J. Immunol. 163, 5497–5504
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.
About this article
Cite this article
Bogdan, C. Nitric oxide and the immune response. Nat Immunol 2, 907–916 (2001). https://doi.org/10.1038/ni1001-907
Inhaled nitric oxide: role in the pathophysiology of cardio-cerebrovascular and respiratory diseases
Intensive Care Medicine Experimental (2022)
Histidine acid phosphatase domain-containing protein from Haemonchus contortus is a stimulatory antigen for the Th1 immune response of goat PBMCs
Parasites & Vectors (2022)
Journal of Translational Medicine (2022)
Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer
Cell Death & Disease (2022)
Cellular & Molecular Immunology (2022)