Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System

Christian Bogdan

doi:10.1128/9781555816872.ch5

Chapter 5 : Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System

VIEW AFFILIATIONS HIDE AFFILIATIONS

Affiliations: 1: Microbiology Institute, Clinical Microbiology, Immunology and Hygiene, Friedrich Alexander University, Erlangen, Nuremberg, and University Clinic of Erlangen Wasserturmstraβe 3/5, D-91054 Erlangen, Germany

Content Type: Monograph

Publication Year: 2011

Category: Immunology; Clinical Microbiology

Book DOI: 10.1128/9781555816872

Chapter DOI: 10.1128/9781555816872.ch5

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap05-1.gif /docserver/preview/fulltext/10.1128/9781555816872/9781555815141_Chap05-2.gif

Abstract:

This chapter reviews the sites of production and the functional diversity of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) within the immune system with a special emphasis on their host-protective effector and regulator potential. The chapter also deals with the expression and function of Inducible nitric oxide synthase (iNOS). In macrophages, iNOS protein and activity has been detected in three different locations: in the cytosol; in a membranous (particulate) compartment consisting of 50 to 80 nm vesicles; and in the cortical actin cytoskeleton immediately beneath the plasma membrane. The role of ROI and RNI in the immune system is unpleasantly ambiguous: They function as aggressive oxidants that kill microbial intruders and, at the same time, cause collateral damage to host tissues; and they serve as signaling molecules that not only control and tune the immune system, but also alarm the infectious pathogen to switch on mechanisms for protection against the host defense machinery. Therefore, ROI and RNI are potentially beneficial and detrimental at the same time, depending on their concentration, on the tissue microenvironment and the time course of generation, and certainly also on the chemistry of the individual products.

Citation: Bogdan C. 2011. Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System, p 69-84. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch5

Key Concept Ranking

Type II Nitric Oxide Synthase: 0.40927497

0.40927497

Highlighted Text: Show | Hide

Full text loading...

Figures

Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555816872.ch05-1,webId=/content/author/10.1128/9781555816872.ch05-1,properties={foaf_givenname=Christian, foaf_name=Christian Bogdan, foaf_surname=Bogdan, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555816872.ch05-aff1]]}]]

/content/10.1128/9781555816872.ch05.ch05fig01

FIGURE 1

Schematic overview of antimicrobial effector mechanisms of neutrophils and other phagocytes. In resting neutrophils gp91phox (NOX2) and p22phox are located in the plasma membrane (depicted) as well as in the membrane of secondary and tertiary granules (not depicted), all of which can contribute to the formation of phagosomes. Upon stimulation (e.g. exposure to pathogens [black oval], crosslinking of Fcγ-receptors by opsonized particles) the Rho-GTPase Rac (Rac1 or Rac2 depending on the cell-type and species) and p47phox in the cytosol become activated by CARD9-mediated release of GDP-dissociation inhibitor (GDI) and subsequent guanine nucleotide exchange factor (GEF)-mediated exchange of GDP for GTP and by phosphorylation (asteriks), respectively, and translocate to the membrane. Subsequent translocation of p67phox and p40phox leads to the enzymatically active phagocyte NADPH oxidase complex, which generates O2 – on the cell surface or within the phagosome. The O2 – is converted into H2O2, either spontaneously by the acidic pH in phagolysosomes, or by host- or pathogen-derived superoxide dismutases (SOD). The iron-dependent Haber-Weiss-reaction (HWR), catalase (Cat) and myeloperoxidase (MPO) help to generate further species of ROI, all of which contribute to the killing of the pathogens (dashed oval). Inducible nitric oxide synthase (iNOS or NOS2), which is found in the cytosol (not depicted) as well as in a vesicular compartment (nitroxosomes) of macrophages and granulocytes, generates citrulline and nitric oxide (NO) from the amino acid L-arginine and molecular oxygen. Neutrophils contain large numbers of primary, secondary and tertiary granules, which are loaded with a broad spectrum of antimicrobially active compounds (see Table 1 for abbreviations and details).

10.1128/9781555816872/f0071-01_thmb.gif

10.1128/9781555816872/f0071-01.gif

FIGURE 1

/content/10.1128/9781555816872.ch05.ch05fig02

FIGURE 2

Generation of nitric oxide from L-arginine by nitric oxide synthases (NOS). Only those cofactors are depicted, which are directly involved in the flux of electrons. The initial product of the reaction is not free ·NO, but a ferric heme-NO complex (not depicted). For further details see text.

10.1128/9781555816872/f0076-01_thmb.gif

10.1128/9781555816872/f0076-01.gif

FIGURE 2

/content/10.1128/9781555816872.ch05.ch05fig03

FIGURE 3

Conceptual framework for iNOS-dependent effects in the immune system (for details see text).

10.1128/9781555816872/f0078-01_thmb.gif

10.1128/9781555816872/f0078-01.gif

FIGURE 3

Conceptual framework for iNOS-dependent effects in the immune system (for details see text).

References

/content/book/10.1128/9781555816872.ch05

1. Adachi, Y.,, A. L. Kindzelskii,, A. R. Petty,, J. B. Huang,, N. Maeda,, S. Yotsumoto,, Y. Aratani,, N. Ohno, and, H. R. Petty. 2006. IFN-gamma primes RAW264 macrophages and human monocytes for enhanced oxidant production in response to CpG DNA via metabolic signaling: roles of TLR9 and myeloperoxidase trafficking. J. Immunol. 176: 5033– 5040.

2. Amezaga, M. A.,, F. Bazzoni,, C. Sorio,, F. Rossi, and, M. A. Cassatella. 1992. Evidence for the involvement of distinct signal transduction pathways in then regulation of constitutive and interferon-g-dependent gene expression of NADPH oxidase components (gp91 phox, p47 phox and p22 phox) and high-affinity receptor for IgG (FcgRI) in human polymorphonuclear leukocytes. Blood 79: 735– 744.

3. Axelrod, S.,, H. Oschkinat,, J. Enders,, B. Schlegel,, V. Brinkmann,, S. H. Kaufmann,, A. Haas, and, U. E. Schaible. 2008. Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide. Cell Microbiol. 10: 1530– 1545.

4. Babior, B. M. 1999. NADPH oxidase: an update. Blood 93: 1464– 1476.

5. Bailey, A.,, T. W. Pope,, S. A. Moore, and, C. L. Campbell. 2007. The tragedy of TRIUMPH for nitric oxide synthesis inhibition in cardiogenic shock: where do we go from here? Am. J. Cardiovasc. Drugs 7: 337– 345.

6. Barraud, N.,, D. J. Hassett,, S. H. Hwang,, S. A. Rice,, S. Kjelleberg, and, J. S. Webb. 2006. Involvement of nitric oxide in biofilm dispersal of Pseudomonas aeruginosa. J. Bacteriol. 188: 7344– 7353.

7. Basu, S.,, R. Grubina,, J. Huang,, J. Conradie,, Z. Huang,, A. Jeffers,, A. Jiang,, X. He,, I. Azarov,, R. Seibert,, A. Mehta,, R. Patel,, S. B. King,, N. Hogg,, A. Ghosh,, M. T. Gladwin, and, D. B. Kim-Shapiro. 2007. Catalytic generation of N 2O 3 by the concerted nitrite reductase and anhydrase activity of hemoglobin. Nat. Chem. Biol. 3: 785– 794.

8. Bedard, K., and, K. H. Krause. 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87: 245– 313.

9. Birkner, K.,, B. Steiner,, C. Rinkler,, Y. Kern,, P. Aichele,, C. Bogdan, and, F. D. von Loewenich. 2008. The elimination of Anaplasma phagocytophilum requires CD4+ T cells, but is independent of Th1 cytokines and a wide spectrum of effector mechanisms. Eur. J. Immunol. 38: 3395– 3410.

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

11. Bogdan, C. 2001a. Nitric oxide and the immune response. Nat. Immunol. 2: 907– 916.

12. Bogdan, C. 2001b. Nitric oxide and the regulation of gene expression. Trends in Cell. Biol. 11: 66– 75.

13. Bogdan, C. 2004. Reactive oxygen and reactive nitrogen metabolites as effector molecules against infectious pathogens, p. 357–396. In S. H. E. Kaufmann,, R. Medzhitov, and, S. Gordon (ed.), The Innate Immune Response to Infection. ASM Press, Washington, D.C.

14. Bogdan, C. 2007a. Oxidative burst without phagocytes: the role of respiratory proteins. Nat. Immunol. 8: 1029– 1031.

15. Bogdan, C. 2007b. Phagocyte effector functions against Leishmania parasites, p. 193–206. In E. D. A. R. Gazzinelli (ed.), Protozoans in Macrophages. Landes Bioscience, Austin, TX.

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

17. Borregaard, N.,, J. H. Schwartz, and, A. I. Tauber. 1984. Proton secretion by stimulated neutrophils. Significance of hexose monophosphate shunt activity as source of electrons and protons for the respiratory burst. J. Clin. Invest. 74: 455– 459.

18. Brechard, S., and, E. J. Tschirhart. 2008. Regulation of superoxide production in neutrophils: role of calcium influx. J. Leukoc. Biol. 84: 1223– 1237.

19. Bronte, V., and, P. Zanovello. 2005. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5: 641– 653.

20. Brown, D. I., and, K. K. Griendling. 2009. Nox proteins in signal transduction. Free Radic. Biol. Med. 47: 1239– 1253.

21. Brown, J. R.,, D. Goldblatt,, J. Buddle,, L. Morton, and, A. J. Thrasher. 2003. Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD). J. Leukoc. Biol. 73: 591– 599.

22. Brune, B. 2003. Nitric oxide: NO apoptosis or turning it ON? Cell Death Differ. 10: 864– 869.

23. Bussiere, F. I.,, R. Chaturvedi,, Y. Cheng,, A. P. Gobert,, M. Asim,, D. R. Blumberg,, H. Xu,, P. Y. Kim,, A. Hacker,, R. A. Casero, Jr., and, K. T. Wilson. 2005. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation. J. Biol. Chem. 280: 2409– 2412.

24. Bussmeyer, U.,, A. Sarkar,, K. Broszat,, T. Ludemann,, S. Moller,, G. van Zandbergen,, C. Bogdan,, M. Behnen,, J. S. Dumler,, F. D. von Loewenich,, W. Solbach, and, T. Laskay. 2010. Impairment of gamma interferon signaling in human neutrophils infected with Anaplasma phagocytophilum. Infect. Immun. 78: 358– 363.

25. Casbon, A. J.,, L. A. Allen,, K. W. Dunn, and, M. C. Dinauer. 2009. Macrophage NADPH oxidase flavocytochrome B localizes to the plasma membrane and Rab11-positive recycling endosomes. J. Immunol. 182: 2325– 2339.

26. Cerenius, L., and, K. Söderhall. 2004. The prophenoloxidase-activating system in invertebrates. Immunol. Reviews 198: 116– 126.

27. Choy, J. C., and, J. S. Pober. 2009. Generation of NO by bystander human CD8 T cells augments allogeneic responses by inhibiting cytokine deprivation-induced cell death. Am. J. Transplant 9: 2281– 2291.

28. Clark, R. A. 1999. Activation of the neutrophil respiratory burst oxidase. J. Infect. Dis. 179: S309– S317.

29. Dai, R.,, R. A. Phillips,, Y. Zhang,, D. Khan,, O. Crasta, and, S. A. Ahmed. 2008. Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood 112: 4591– 4597.

30. Daniel, T.,, M. Alexander,, W. J. Hubbard,, I. H. Chaudry,, M. A. Choudhry, and, M. G. Schwacha. 2006. Nitric oxide contributes to the development of a post-injury Th2 T-cell phenotype and immune dysfunction. J. Cell Physiol. 208: 418– 427.

31. Das, P.,, A. Lahiri,, A. Lahiri, and, D. Chakravortty. 2009. Novel role of the nitrite transporter NirC in Salmonella pathogenesis: SPI2-dependent suppression of inducible nitric oxide synthase in activated macrophages. Microbiology 155: 2476– 2489.

32. De Trez, C.,, S. Magez,, S. Akira,, B. Ryffel,, Y. Carlier, and, E. Muraille. 2009. iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS Pathog. 5: e1000494.

33. Ding, A. H.,, C. F. Nathan, and, D. J. Stuehr. 1988. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J. Immunol. 141: 2407– 2412.

34. Donaldson, M.,, A. Antignani,, J. Milner,, N. Zhu,, A. Wood,, L. Cardwell-Miller,, C. M. Changpriroa, and, S. H. Jackson. 2009. p47phox-deficient immune microenvironment signals dysregulate naive T-cell apoptosis. Cell Death Differ. 16: 125– 138.

35. Donko, A.,, Z. Peterfi,, A. Sum,, T. Leto, and, M. Geiszt. 2005. Dual oxidases. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 360: 2301– 2308.

36. Duan, J.,, F. Y. Avci, and, D. L. Kasper. 2008. Microbial carbohydrate depolymerization by antigen-presenting cells: deamination prior to presentation by the MHCII pathway. Proc. Natl. Acad. Sci. USA 105: 5183– 5188.

37. Eiserich, J. P.,, S. Baldus,, M.-L. Brennan,, W. Ma,, C. Zhang,, A. Tousson,, L. Castro,, A. J. Lusis,, W. M. Nauseef,, C. R. White, and, B. A. Freeman. 2002. Myeloperoxidase, a leukocyte-derived vascular NO synthase. Science 296: 2391– 2394.

38. Fabrino, D. L.,, C. K. Bleck,, E. Anes,, A. Hasilik,, R. C. Melo,, M. Niederweis,, G. Griffiths, and, M. G. Gutierrez. 2009. Porins facilitate nitric oxide-mediated killing of mycobacteria. Microbes Infect. 11: 868– 875.

39. Fang, F. C. 2004. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat. Rev. Immunol. 2: 820– 832.

40. Fang, F. C., and, C. F. Nathan. 2007. Man is not a mouse: reply. J. Leukoc. Biol. 81: 580.

41. Feinberg, M. W.,, Z. Cao,, A. K. Wara,, M. A. Lebedeva,, S. Senbanerjee, and, M. K. Jain. 2005. Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages. J. Biol. Chem. 280: 38247– 38258.

42. Fernandez-Arenas, E.,, C. K. Bleck,, C. Nombela,, C. Gil,, G. Griffiths, and, R. Diez-Orejas. 2009. Candida albicans actively modulates intracellular membrane trafficking in mouse macrophage phagosomes. Cell Microbiol. 11: 560– 589.

43. Fernandez-Boyanapalli, R. F.,, S. C. Frasch,, K. McPhillips,, R. W. Vandivier,, B. L. Harry,, D. W. Riches,, P. M. Henson, and, D. L. Bratton. 2009. Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4. Blood 113: 2047– 2055.

44. Ferrer-Sueta, G., and, R. Radi. 2009. Chemical biology of peroxynitrite: kinetics, diffusion, and radicals. ACS Chem. Biol. 4: 161– 177.

45. Forman, H. J., and, M. Torres. 2001. Redox signaling in macrophages. Mol. Asp. Med. 22: 189– 216.

46. Fuchs, T. A.,, U. Abed,, C. Goosmann,, R. Hurwitz,, I. Schulze,, V. Wahn,, Y. Weinrauch,, V. Brinkmann, and, A. Zychlinsky. 2007. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176: 231– 241.

47. Gabig, T. G.,, S. I. Bearman, and, B. M. Babior. 1979. Effects of oxygen tension and pH on the respiratory burst of human neutrophils. Blood 53: 1133– 1139.

48. Garcia-Garcia, J. C.,, N. C. Barat,, S. J. Trembley, and, J. S. Dumler. 2009. Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathog. 5: e1000488.

49. Gaur, U.,, S. C. Roberts,, R. P. Dalvi,, I. Corraliza,, B. Ullman, and, M. E. Wilson. 2007. An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. J. Immunol. 179: 8446– 8453.

50. Gaziano, J. M.,, R. J. Glynn,, W. G. Christen,, T. Kurth,, C. Belanger,, J. MacFadyen,, V. Bubes,, J. E. Manson,, H. D. Sesso, and, J. E. Buring. 2009. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. Jama 301: 52– 62.

51. Geiszt, M.,, A. Kapus,, K. Nemet,, L. Farkas, and, E. Ligeti. 1997. Regulation of capacitative Ca2+ influx in human neutrophil granulocytes. Alterations in chronic granulomatous disease. J. Biol. Chem. 272: 26471– 26478.

52. Geiszt, M.,, J. Witta,, J. Baffi,, K. Lekstrom, and, T. L. Leto. 2003. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 17: 1502– 1504.

53. Gelderman, K. A.,, M. Hultqvist,, L. M. Olsson,, K. Bauer,, A. Pizzolla,, P. Olofsson, and, R. Holmdahl. 2007a. Rheumatoid arthritis: the role of reactive oxygen species in disease development and therapeutic strategies. Antioxid. Redox. Signal 9: 1541– 1567.

54. Gelderman, K. A.,, M. Hultqvist,, A. Pizzolla,, M. Zhao,, K. S. Nandakumar,, R. Mattsson, and, R. Holmdahl. 2007b. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J. Clin. Invest. 117: 3020– 3028.

55. Gloire, G.,, S. Legrand-Poels, and, J. Piette. 2006. NF-kappaB activation by reactive oxygen species: fifteen years later. Bio-chem. Pharmacol. 72: 1493– 1505.

56. Gomes, M. S.,, S. Sousa Fernandes,, J. V. Cordeiro,, S. Silva Gomes, A. Vieira, and, R. Appelberg. 2008. Engagement of Toll-like receptor 2 in mouse macrophages infected with Mycobacterium avium induces non-oxidative and TNF-independent antimycobacterial activity. Eur. J. Immunol. 38: 2180– 2189.

57. Griffiths, H. R. 2008. Is the generation of neo-antigenic determinants by free radicals central to the development of autoimmune rheumatoid disease? Autoimmun. Rev. 7: 544– 549.

58. Hancock, J. T.,, R. Desikan, and, S. J. Neill. 2001. Role of reactive oxygen species in cell signalling pathways. Biochem. Soc. Trans. 29: 345– 350.

59. Harrison, C. A.,, M. J. Raftery,, J. Walsh,, P. Alewood,, S. E. Iismaa,, S. Thliveris, and, C. L. Geczy. 1999. Oxidation regulates the inflammatory properties of the murine S100 protein S100A8. J. Biol. Chem. 274: 8561– 8569.

60. Hoarau, C.,, B. Gerard,, E. Lescanne,, D. Henry,, S. Francois,, J. J. Lacapere,, J. El Benna,, P. M. Dang,, B. Grandchamp,, Y. Lebranchu,, M. A. Gougerot-Pocidalo, and, C. Elbim. 2007. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J. Immunol. 179: 4754– 4765.

61. Hotopp, J. C.,, M. Lin,, R. Madupu,, J. Crabtree,, S. V. Angiuoli,, J. Eisen,, R. Seshadri,, Q. Ren,, M. Wu,, T. R. Utterback,, S. Smith,, M. Lewis,, H. Khouri,, C. Zhang,, H. Niu,, Q. Lin,, N. Ohashi,, N. Zhi,, W. Nelson,, L. M. Brinkac,, R. J. Dodson,, M. J. Rosovitz,, J. Sundaram,, S. C. Daugherty,, T. Davidsen,, A. S. Durkin,, M. Gwinn,, D. H. Haft,, J. D. Selengut,, S. A. Sullivan,, N. Zafar,, L. Zhou,, F. Benahmed,, H. Forberger,, R. Halpin,, S. Mulligan,, J. Robinson,, O. White,, Y. Rikihisa, and, H. Tettelin. 2006. Comparative genomics of emerging human ehrlichiosis agents. PLoS Genet. 2: e21.

62. Huang, D.,, D. T. Cai,, R. Y. Chua,, D. M. Kemeny, and, S. H. Wong. 2008. Nitric-oxide synthase 2 interacts with CD74 and inhibits its cleavage by caspase during dendritic cell development. J. Biol. Chem. 283: 1713– 1722.

63. Hultqvist, M.,, L. M. Olsson,, K. A. Gelderman, and, R. Holmdahl. 2009. The protective role of ROS in autoimmune disease. Trends Immunol. 30: 201– 208.

64. Ibiza, S.,, A. Perez-Rodriguez,, A. Ortega,, A. Martinez-Ruiz,, O. Barreiro,, C. A. Garcia-Dominguez,, V. M. Victor,, J. V. Esplugues,, J. M. Rojas,, F. Sanchez-Madrid, and, J. M. Serrador. 2008. Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells. Proc. Natl. Acad. Sci. USA 105: 10507– 10512.

65. Iniesta, V.,, L. C. Gomez-Nieto, and, I. Corraliza. 2001. The inhibition of arginase by Nw-hydroxy-L-arginine controls the growth of Leishmania inside macrophages. J. Exp. Med. 193: 777– 783.

66. Into, T.,, M. Inomata,, M. Nakashima,, K. Shibata,, H. Hacker, and, K. Matsushita. 2008. Regulation of MyD88-dependent signaling events by S nitrosylation retards toll-like receptor signal transduction and initiation of acute-phase immune responses. Mol. Cell. Biol. 28: 1338– 1347.

67. Jackson, S. H.,, S. Devadas,, J. Kwon,, L. A. Pinto, and, M. S. Williams. 2004. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5: 818– 827.

68. Jesaitis, A. J.,, E. S. Buescher,, D. Harrison,, M. T. Quinn,, C. A. Parkos,, S. Livesey, and, J. Linner. 1990. Ultrastructural localization of cytochrome b in the membranes of resting and phagocytosing human granulocytes. J. Clin. Invest. 85: 821– 835.

69. Jiang, N.,, N. S. Tan,, B. Ho, and, J. L. Ding. 2007. Respiratory proteins generate ROS as an antimicrobial strategy. Nat. Immunol. 8: 1114– 1122.

70. Jones-Carson, J.,, J. Laughlin,, M. A. Hamad,, A. L. Stewart,, M. I. Voskuil, and, A. Vazquez-Torres. 2008. Inactivation of [Fe-S] metalloproteins mediates nitric oxide-dependent killing of Burkholderia mallei. PLoS One 3: e1976.

71. Jones, R. J.,, D. Jourd’heuil, J. C. Salerno,, S. M. Smith, and, H. A. Singer. 2007. iNOS regulation by calcium/calmodulin-dependent protein kinase II in vascular smooth muscle. Am. J. Physiol. Heart Circ. Physiol. 292: H2634– H2642.

72. Kawahara, T.,, M. T. Quinn, and, J. D. Lambeth. 2007. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol. Biol. 7: 109.

73. Kim, C., and, M. C. Dinauer. 2006. Impaired NADPH oxidase activity in Rac2-deficient murine neutrophils does not result from defective translocation of p47phox and p67phox and can be rescued by exogenous arachidonic acid. J. Leukoc. Biol. 79: 223– 234.

74. Kim, M. Y.,, J. H. Park,, J. S. Mo,, E. J. Ann,, S. O. Han,, S. H. Baek,, K. J. Kim,, S. Y. Im,, J. W. Park,, E. J. Choi, and, H. S. Park. 2008. Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide. J. Cell Sci. 121: 1466– 1476.

75. Kjeldsen, L.,, H. Sengelov,, K. Lollike,, M. H. Nielsen, and, N. Borregaard. 1994. Isolation and characterization of gelatinase granules from human neutrophils. Blood 83: 1640– 1649.

76. Klebanoff, S. J. 1999. Oxygen metabolites from phagocytes, p. 721–768. In J. I. Gallin, and, R. Snyderman (eds.), Inflammation: Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia, PA.

77. Kleinert, H.,, A. Pautz,, K. Linker, and, P. M. Schwarz. 2004. Regulation of the expression of inducible nitric oxide synthase. Eur. J. Pharmacol. 500: 255– 566.

78. Kobayashi, T.,, J. M. Robinson, and, H. Seguchi. 1998. Identification of intracellular sites of superoxide production in stimulated neutrophils. J. Cell Science 111: 81– 91.

79. Kolodziejski, P.,, A. Musial,, J.-S. Koo, and, N. T. Eissa. 2002. Ubiquitination of inducible nitric oxide synthase is required for its degradation. Proc. Natl. Acad. Sci. USA 99: 12315– 12320.

80. König, T.,, C. Bogdan, and, U. Schleicher. 2009. Translational repression of inducible NO synthase in macrophages by L-arginine depletion is not associated with an increased phosphorylation of eIF2alpha. Immunobiology 214: 822– 827.

81. Korhonen, R.,, K. Linker,, A. Pautz,, U. Forstermann,, E. Moilanen, and, H. Kleinert. 2007. Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the Jun N-terminal kinase. Mol. Pharmacol. 71: 1427– 1434.

82. Kropf, P.,, J. M. Fuentes,, E. Fahnrich,, L. Arpa,, S. Herath,, V. Weber,, G. Soler,, A. Celada,, M. Modolell, and, I. Müller. 2005. Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J. 19: 1000– 1002.

83. Kusmartsev, S.,, Y. Nefedova,, D. Yoder, and, D. I. Gabrilovich. 2004. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172: 989– 999.

84. Lambeth, J. D.,, T. Kawahara, and, B. Diebold. 2007. Regulation of Nox and Duox enzymatic activity and expression. Free Radic. Biol. Med. 43: 319– 331.

85. Laver, J. R.,, T. M. Stevanin,, S. L. Messenger,, A. D. Lunn,, M. E. Lee,, J. W. Moir,, R. K. Poole, and, R. C. Read. 2009. Bacterial nitric oxide detoxification prevents host cell S-nitrosothiol formation: a novel mechanism of bacterial pathogenesis. FASEB J. 24: 286– 295.

86. Lekstrom-Himes, J. A.,, D. B. Kuhns,, W. G. Alvord, and, J. I. Gallin. 2005. Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease. J. Immunol. 174: 411— 417.

87. Li, Y.,, J. Yan,, P. De,, H. C. Chang,, A. Yamauchi,, K. W. Christopherson, 2nd,, N. C. Paranavitana,, X. Peng,, C. Kim,, V. Munugalavadla,, R. Kapur,, H. Chen,, W. Shou,, J. C. Stone,, M., H. Kaplan,, M. C. Dinauer,, D. L. Durden, and, L. A. Quilliam. 2007. Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. J. Immunol. 179: 8322– 8331.

88. Lippman, S. M.,, E. A. Klein,, P. J. Goodman,, M. S. Lucia,, I. M. Thompson,, L. G. Ford,, H. L. Parnes,, L. M. Minasian,, J. M. Gaziano,, J. A. Hartline,, J. K. Parsons,, J. D. Bearden, III,, E. D. Crawford,, G. E. Goodman,, J. Claudio,, E. Winquist,, E. D. Cook,, D. D. Karp,, P. Walther,, M. M. Lieber,, A. R. Kristal,, A. K. Darke,, K. B. Arnold,, P. A. Ganz,, R. M. Santella,, D. Albanes,, P. R. Taylor,, J. L. Probstfield,, T. J. Jagpal,, J. J. Crowley,, F. L. Meyskens, Jr.,, L. H. Baker, and, C. A. Coltman, Jr. 2009. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Jama 301: 39– 51.

89. Marigo, I.,, L. Dolcetti,, P. Serafini,, P. Zanovello, and, V. Bronte. 2008. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 222: 162– 179.

90. Martinon, F.,, A. Mayor, and, J. Tschopp. 2009. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27: 229– 265.

91. McCollister, B. D.,, T. J. Bourret,, R. Gill,, J. Jones-Carson, and, A. Vazquez-Torres. 2005. Repression of SPI2 transcription by nitric oxide-producing, IFNgamma-activated macrophages promotes maturation of Salmonella phagosomes. J. Exp. Med. 202: 625– 635.

92. Metzger, Z.,, J. T. Hoffeld, and, J. J. Oppenheim. 1980. Macrophage-mediated suppression I. Evidence for the participation of both hydrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J. Immunol. 124: 983– 988.

93. Mitani, T.,, M. Terashima,, H. Yoshimura,, Y. Nariai, and, Y. Tanigawa. 2005. TGF-beta1 enhances degradation of IFN-gamma-induced iNOS protein via proteasomes in RAW 264.7 cells. Nitric Oxide 13: 78– 87.

94. Modolell, M.,, B. S. Choi,, R. O. Ryan,, M. Hancock,, R. G. Titus,, T. Abebe,, A. Hailu,, I. Muller,, M. E. Rogers,, C. R. Bangham,, M. Munder, and, P. Kropf. 2009. Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis. PLoS Negl. Trop. Dis. 3: e480.

95. Morris, S. M., Jr. 2009. Recent advances in arginine metabolism: roles and regulation of the arginases. Br. J. Pharmacol. 157: 922– 930.

96. Muleme, H. M.,, R. M. Reguera,, A. Berard,, R. Azinwi,, P. Jia,, I. B. Okwor,, S. Beverley, and, J. E. Uzonna. 2009. Infection with arginase-deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis. J. Immunol. 183: 8068– 8076.

97. Munafo, D. B.,, J. L. Johnson,, A. A. Brzezinska,, B. A. Ellis,, M. R. Wood, and, S. D. Catz. 2009. DNAse I inhibits a late phase of reactive oxygen species production in neutrophils. J. Innate Immun. 1: 527– 542.

98. Myers, J. T.,, A. W. Tsang, and, J. A. Swanson. 2003. Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages. J. Immunol. 171: 5447– 5453.

99. Nagaraj, S.,, M. Collazo,, C. A. Corzo,, J. I. Youn,, M. Ortiz,, D. Quiceno, and, D. I. Gabrilovich. 2009. Regulatory myeloid suppressor cells in health and disease. Cancer Res. 69: 7503– 7506.

100. Nathan, C. 2003. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J. Clin. Invest. 111: 769– 778.

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

102. Nauseef, W. M. 2008a. Biological roles for the NOX family NADPH oxidases. J. Biol. Chem. 283: 16961– 16965.

103. Nauseef, W. M. 2008b. Nox enzymes in immune cells. Semin. Immunopathol. 30: 195– 208.

104. Niedbala, W.,, B. Cai,, H. Liu,, N. Pitman,, L. Chang, and, F. Y. Liew. 2007. Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40. Proc. Natl. Acad. Sci. USA 104: 15478– 15483.

105. Niedbala, W.,, X.-q. Wei,, C. Campbell,, D. Thomson,, M. Komai-Koma, and, F. Y. Liew. 2002. Nitric oxide preferentially induces type 1 T cell differentiation by selectively up-regulating IL-12 receptor b2 expression via cGMP. Proc. Natl. Acad. Sci. USA 99: 16186– 16191.

106. Niethammer, P.,, C. Grabher,, A. T. Look, and, T. J. Mitchison. 2009. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebra fish. Nature 459: 996– 999.

107. Norman, M. U.,, L. Zbytnuik, and, P. Kubes. 2008. Interferon-gamma limits Th1 lymphocyte adhesion to inflamed en-dothelium: a nitric oxide regulatory feedback mechanism. Eur. J. Immunol. 38: 1368– 1380.

108. Ogier-Denis, E.,, S. B. Mkaddem, and, A. Vandewalle. 2008. NOX enzymes and Toll-like receptor signaling. Semin. Immunopathol. 30: 291– 300.

109. Owusu-Ansah, E., and, U. Banerjee. 2009. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461: 537– 541.

110. Pacquelet, S.,, J. L. Johnson,, B. A. Ellis,, A. A. Brzezinska,, W. S. Lane,, D. B. Munafo, and, S. D. Catz. 2007. Cross-talk between IRAK-4 and the NADPH oxidase. Biochem. J. 403: 451– 461.

111. Pandit, L.,, K. E. Kolodziejska,, S. Zeng, and, N. T. Eissa. 2009. The physiologic aggresome mediates cellular inactivation of iNOS. Proc. Natl. Acad. Sci. USA 106: 1211– 1215.

112. Park, J.-W.,, C.-H. Kim,, J.-H. Kim,, B.-R. Je,, K.-B. Roh,, S.-J. Kim,, H.-H. Lee,, J.-H. Ryu,, J.-H. Lim,, B.-H. Oh,, W.-J. Lee, and, L. Bok-Luel. 2007. Clustering of peptidoglycan recognition protein-SA is required for sensing lysine-type peptidoglycan in sects. Proc. Natl. Acad. Sci. USA 104: 6602– 6607.

113. Parsa, K. V.,, J. P. Butchar,, M. V. Rajaram,, T. J. Cremer,, J. S. Gunn,, L. S. Schlesinger, and, S. Tridandapani. 2008. Francisella gains a survival advantage within mononuclear phagocytes by suppressing the host IFNgamma response. Mol. Immunol. 45: 3428– 3437.

114. Prokopowicz, Z. M.,, F. Arce,, R. Biedron,, C. L. Chiang,, M. Ciszek,, D. R. Katz,, M. Nowakowska,, S. Zapotoczny,, J. Marcinkiewicz, and, B. M. Chain. 2009. Hypochlorous acid: a natural adjuvant that facilitates antigen processing, cross-priming, and the induction of adaptive immunity. J. Immunol. 184: 825– 835.

115. Purushothaman, D., and, A. Sarin. 2009. Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis. J. Exp. Med. 206: 1515– 1523.

116. Purwantini, E., and, B. Mukhopadhyay. 2009. Conversion of NO 2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage. Proc. Natl. Acad. Sci. USA 106: 6333– 6338.

117. Quinn, M. T., and, I. A. Schepetkin. 2009. Role of NADPH oxidase in formation and function of multinucleated giant cells. J. Innate Immun. 1: 509– 526.

118. Rabelink, T. J., and, T. F. Luscher. 2006. Endothelial nitric oxide synthase: host defense enzyme of the endothelium? Arterioscler Thromb. Vasc. Biol. 26: 267– 271.

119. Rajakariar, R.,, J. Newson,, E. K. Jackson,, P. Sawmynaden,, A. Smith,, F. Rahman,, M. M. Yaqoob, and, D. W. Gilroy. 2009. Nonresolving inflammation in gp91phox-/- mice, a model of human chronic granulomatous disease, has lower adenosine and cyclic adenosine 5′-monophosphate. J. Immunol. 182: 3262– 3269.

120. Reeves, E. P.,, H. Lu,, H. L. Jacobs,, C. G. M. Messina,, S. Bolsover,, G. Gabella,, E. O. Potma,, A. Warley,, J. Roes, and, A. W. Segal. 2002. Killing activity of neutrophils is mediated through activation of proteases by K + flux. Nature 416: 291.

121. Reguera, R. M.,, R. Balana-Fouce,, M. Showalter,, S. Hickerson, and, S. M. Beverley. 2009. Leishmania major lacking arginase (ARG) are auxotrophic for polyamines but retain infectivity to susceptible BALB/c mice. Mol. Biochem. Parasitol. 165: 48– 56.

122. Ren, G.,, J. Su,, X. Zhao,, L. Zhang,, J. Zhang,, A. I. Roberts,, H. Zhang,, G. Das, and, Y. Shi. 2008. Apoptotic cells induce immunosuppression through dendritic cells: critical roles of IFN-gamma and nitric oxide. J. Immunol. 181: 3277– 3284.

123. Reth, M. 2002. Hydrogen peroxide as second messenger in lymphocyte activation. Nat. Immunol. 3: 1129– 1134.

124. Rodriguez, P. C.,, D. G. Quiceno, and, A. C. Ochoa. 2007. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109: 1568– 1573.

125. Rodriguez, P. C.,, A. H. Zea,, J. DeSalvo,, K. S. Culotta,, J. Zabaleta,, D. G. Quiceno,, J. B. Ochoa, and, A. C. Ochoa. 2003. L-arginine consumption by macrophages modulates the expression of CD3z chain in T lymphocytes. J. Immunol. 17: 1232– 1239.

126. Romani, L.,, F. Fallarino,, A. De Luca, C. Montagnoli,, C. D’Angelo,, T. Zelante,, C. Vacca,, F. Bistoni,, M. C. Fioretti,, U. Grohmann,, B. H. Segal, and, P. Puccetti. 2008. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451: 211– 215.

127. Rommel, C.,, M. Camps, and, H. Ji. 2007. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat. Rev. Immunol. 7: 191– 201.

128. Sanmun, D.,, E. Witasp,, S. Jitkaew,, Y. Y. Tyurina,, V. E. Kagan,, A. Ahlin,, J. Palmblad, and, B. Fadeel. 2009. Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease. Am. J. Physiol. Cell Physiol. 297: C621– C631.

129. Savina, A.,, A. Peres,, I. Cebrian,, N. Carmo,, C. Moita,, N. Hacohen,, L. F. Moita, and, S. Amigorena. 2009. The small GTPase Rac2 controls phagosomal alkalinization and antigen crosspresentation selectively in CD8(+) dendritic cells. Immunity 30: 544– 555.

130. Schappi, M. G.,, V. Jaquet,, D. C. Belli, and, K. H. Krause. 2008. Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase. Semin. Immunopathol. 30: 255– 271.

131. Segal, A. W. 2005. How neutrophils kill microbes. Annu. Rev. Immunol. 23: 197– 223.

132. Segal, A. W.,, M. Geisow,, R. Garcia,, A. Harper, and, R. Miller. 1981. The respiratory burst of phagocytic cells is associated with a rise in vacuolar pH. Nature 290: 406– 409.

133. Sen, C. K., and, S. Roy. 2008. Redox signals in wound healing. Biochim. Biophys. Acta 1780: 1348– 1361.

134. Serbina, N. V.,, T. P. Salazar-Mather,, C. A. Biron,, W. A. Kuziel, and, E. G. Pamer. 2003. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19: 59– 70.

135. Sharma, P.,, R. Chakraborty,, L. Wang,, B. Min,, M. L. Tremblay,, T. Kawahara,, J. D. Lambeth, and, S. J. Haque. 2008. Redox regulation of interleukin-4 signaling. Immunity 29: 551– 564.

136. Shatalin, K.,, I. Gusarov,, E. Avetissova,, Y. Shatalina,, L. E. McQuade,, S. J. Lippard, and, E. Nudler. 2008. Bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages. Proc. Natl. Acad. Sci. USA 105: 1009– 1013.

137. Singh, A.,, K. A. Zarember,, D. B. Kuhns, and, J. I. Gallin. 2009. Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. J. Immunol. 182: 6410– 6417.

138. Singh, R.,, U. Manjunatha,, H. I. Boshoff,, Y. H. Ha,, P. Niyomrattanakit,, R. Ledwidge,, C. S. Dowd,, I. Y. Lee,, P. Kim,, L. Zhang,, S. Kang,, T. H. Keller,, J. Jiricek, and, C. E. Barry, III. 2008. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 322: 1392– 135.

139. Snelgrove, R. J.,, L. Edwards,, A. J. Rae, and, T. Hussell. 2006. An absence of reactive oxygen species improves the resolution of lung influenza infection. Eur. J. Immunol. 36: 1364– 1373.

140. Soderberg, M.,, F. Raffalli-Mathieu, and, M. A. Lang. 2007. Identification of a regulatory cis-element within the 3′-untranslated region of the murine inducible nitric oxide synthase (iNOS) mRNA; interaction with heterogeneous nuclear ribonucleoproteins I and L and role in the iNOS gene expression. Mol. Immunol. 44: 434– 442.

141. Sorce, S., and, K. H. Krause. 2009. NOX enzymes in the central nervous system: from signaling to disease. Antioxid. Redox. Signal 11: 2481– 2504.

142. Stone, J. R., and, S. Yang. 2006. Hydrogen peroxide: a signaling messenger. Antioxid. Redox. Signal 8: 243– 270.

143. Stuehr, D. J.,, J. Santolini,, Z. Q. Wang,, C. C. Wei, and, S. Adak. 2004. Update on mechanism and catalytic regulation in the NO synthases. J. Biol. Chem. 279: 36167– 36170.

144. Stuehr, D. J.,, J. Tejero, and, M. M. Haque. 2009. Structural and mechanistic aspects of flavoproteins: electron transfer through the nitric oxide synthase flavoprotein domain. Febs. J. 276: 3959– 3974.

145. Sun, J.,, L. J. Druhan, and, J. L. Zweier. 2009. Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production. Arch. Biochem. Biophys. 494: 130– 137.

146. Takaki, H.,, Y. Minoda,, K. Koga,, G. Takaesu,, A. Yoshimura, and, T. Kobayashi. 2006. TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. Genes Cells 11: 871– 882.

147. Urban, C. F.,, D. Ermert,, M. Schmid,, U. Abu-Abed, C. Goosmann, W. Nacken, V. Brinkmann, P. R. Jungblut, and, A. Zychlinsky. 2009. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 5: e1000639.

148. Valdez, C. A.,, J. E. Saavedra,, B. M. Showalter,, K. M. Davies,, T. C. Wilde,, M. L. Citro,, J. J. Barchi, Jr.,, J. R. Deschamps,, D. Parrish,, S. El-Gayar,, U. Schleicher,, C. Bogdan, and, L. K. Keefer. 2008. Hydrolytic Reactivity Trends among Potential Prodrugs of the O(2)-Glycosylated Diazenium-diolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity. J. Med. Chem. 51: 3961– 3970.

149. Vareille, M.,, T. de Sablet,, T. Hindre,, C. Martin, and, A. P. Gobert. 2007. Nitric oxide inhibits Shiga-toxin synthesis by enterohemorrhagic Escherichia coli. Proc. Natl. Acad, Sci, USA 104: 10199– 10204.

150. Vig, M.,, S. Srivastava,, U. Kandpal,, H. Sade,, V. Lewis,, A. Sarin,, A. George,, V. Bal,, J. M. Durdik, and, S. Rath. 2004. Inducible nitric oxide synthase in T cells regulates T cell death and immune memory. J. Clin. Invest. 113: 1734– 1742.

151. Vodovotz, Y.,, C. Bogdan,, J. Paik,, Q.-w. Xie, and, C. Nathan. 1993. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor-β. J. Exp. Med. 178: 605– 613.

152. von Loewenich, F. D.,, D. G. Scorpio,, U. Reischl,, J. S. Dumler, and, C. Bogdan. 2004. Control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR) 2 and 4, or the TLR adaptor molecule MyD88. Eur. J. Immunol. 34: 1789– 1797.

153. Vulcano, M.,, S. Dusi,, D. Lissandrini,, R. Badolato,, P. Mazzi,, E. Riboldi,, E. Borroni,, A. Calleri,, M. Donini,, A. Plebani,, L. Notarangelo,, T. Musso, and, S. Sozzani. 2004. Toll receptor-mediated regulation of NADPH oxidase in human dendritic cells. J. Immunol. 173: 5749– 5756.

154. Wang, X.,, Q. Zhao,, R. Matta,, X. Meng,, X. Liu,, C. G. Liu,, L. D. Nelin, and, Y. Liu. 2009. Inducible nitric-oxide synthase expression is regulated by mitogen-activated protein kinase phosphatase-1. J. Biol. Chem. 284: 27123– 27134.

155. Winberg, M. E.,, B. Rasmusson, and, T. Sundqvist. 2007. Leishmania donovani: inhibition of phagosomal maturation is rescued by nitric oxide in macrophages. Exp. Parasitol. 117: 165– 170.

156. Won, J. S.,, Y. B. Im,, A. K. Singh, and, I. Singh. 2004. Dual role of cAMP in iNOS expression in glial cells and macrophages is mediated by differential regulation of p38-MAPK/ATF-2 activation and iNOS stability. Free Radic. Biol. Med. 37: 1834– 1844.

157. Wu, W.,, Y. M. Hsu,, L. Bi,, Z. Songyang, and, X. Lin. 2009. CARD9 facilitates microbe-elicited production of reactive oxygen species by regulating the LyGDI-Rac1 complex. Nat. Immunol. 10: 1208– 1214.

158. Yamauchi, A.,, C. Kim,, S. Li,, C. C. Marchal,, J. Towe,, S. J. Atkinson, and, M. C. Dinauer. 2004. Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. J. Immunol. 173: 5971– 5979.

159. Yazdanpanah, B.,, K. Wiegmann,, V. Tchikov,, O. Krut,, C. Pongratz,, M. Schramm,, A. Kleinridders,, T. Wunderlich,, H. Kashkar,, O. Utermohlen,, J. C. Bruning,, S. Schutze, and, M. Kronke. 2009. Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460: 1159– 1163.

160. Zhou, L., and, D. Y. Zhu. 2009. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide 20: 223– 230.

Tables

Reactive Oxygen and Reactive Nitrogen Intermediates in the Immune System

/content/10.1128/9781555816872.ch05.ch05tab01

TABLE 1

Antimicrobial effector mechanisms of phagocytes

TABLE 1

Antimicrobial effector mechanisms of phagocytes

/content/10.1128/9781555816872.ch05.ch05tab02

TABLE 2

NADPH-dependent oxidases (NOX/DUOX family) ( Bedard and Krause, 2007 ; Kawahara et al., 2007 ; Lambeth et al., 2007 )

TABLE 2

NADPH-dependent oxidases (NOX/DUOX family) ( Bedard and Krause, 2007 ; Kawahara et al., 2007 ; Lambeth et al., 2007 )