Histochemistry and Cell Biology

, Volume 122, Issue 4, pp 277–291 | Cite as

Assembly of the phagocyte NADPH oxidase

  • William M. NauseefEmail author


Stimulated phagocytes undergo a burst in respiration whereby molecular oxygen is converted to superoxide anion through the action of an NADPH-dependent oxidase. The multicomponent phagocyte oxidase is unassembled and inactive in resting cells but assembles at the plasma or phagosomal membrane upon phagocyte activation. Oxidase components include flavocytochrome b558, an integral membrane heterodimer comprised of gp91phox and p22phox, and three cytosolic proteins, p47phox, p67phox, and Rac1 or Rac2, depending on the species and phagocytic cell. In a sense, the phagocyte oxidase is spatially regulated, with critical elements segregated in the membrane and cytosol but ready to undergo nearly immediate assembly and activation in response to stimulation. To achieve such spatial regulation, the individual components in the resting phagocyte adopt conformations that mask potentially interactive structural domains that might mediate productive intermolecular associations and oxidase assembly. In response to stimulation, post-translational modifications of the oxidase components release these constraints and thereby render potential interfaces accessible and interactive, resulting in translocation of the cytosolic elements to the membrane where the functional oxidase is assembled and active. This review summarizes data on the structural features of the phagocyte oxidase components and on the agonist-dependent conformational rearrangements that contribute to oxidase assembly and activation.


NADPH oxidase Respiratory burst Neutrophils Phagocytes Oxidase assembly 



Work in the Nauseef laboratory is supported by the National Institutes of Health (AI34879, HL53592, and AI44642) and by a Merit Review Grant from the Department of Veterans Affairs.


  1. Abo A, Pick E (1991) Purification and characterization of a third cytosolic component of the superoxide-generating NADPH oxidase of macrophages. J Biol Chem 266:23577–23585PubMedGoogle Scholar
  2. Abo A, Pick E, Hall A, Totty N, Teahan CG, Segal AW (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature 353:668–670CrossRefPubMedGoogle Scholar
  3. Abo A, Webb MR, Grogan A, Segal AW (1994) Activation of NADPH oxidase involves the dissociation of p21rac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. Biochem J 298:585–591PubMedGoogle Scholar
  4. Aderem A, Underhill D (1999) Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17:593–623CrossRefPubMedGoogle Scholar
  5. Ago T, Nunoi H, Ito T, Sumimoto H (1999) Mechanism for phosphorylation-induced activation of the phagocyte NADPH oxidase protein p47phox. J Biol Chem 274:33644–33653CrossRefPubMedGoogle Scholar
  6. Ago T, Takeya R, Hiroaki H, Kuribayashi F, Ito T, Kohda D, Sumimoto H (2001) The PX domain as a novel phosphoinositide-binding module. Biochem Biophys Res Commun 287:733–738CrossRefPubMedGoogle Scholar
  7. Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H (2003) Phosphorylation of p47phox directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation. Proc Natl Acad Sci U S A 100:4474–4479CrossRefPubMedGoogle Scholar
  8. Agwu DE, McPhail LC, Sozzani S, Bass DA, McCall CE (1991) Phosphatidic acid as a second messenger in human polymorphonuclear leukocytes. Effects on activation of NADPH oxidase. J Clin Invest 88:531–539PubMedGoogle Scholar
  9. Allen L-AH, DeLeo FR, Gallois A, Toyoshima S, Suzuki K, Nauseef WM (1999) Transient association of the nicotinamide adenine dinucleotide phosphate oxidase subunits p47phox and p67phox with phagosomes in neutrophils from patients with X-linked chronic granulomatous disease. Blood 93:3521–3530PubMedGoogle Scholar
  10. Alloul N, Gorzalczany Y, Itan M, Sigal N, Pick E (2001) Activation of the superoxide-generating NADPH oxidase by chimeric proteins consisting of segments of the cytosolic component p67phox and the small GTPase Rac1. Biochemistry 40:14557–14566CrossRefPubMedGoogle Scholar
  11. Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, Thurman G, Gonzalez-Aller C, Hiester A, deBoer M, Harbeck RJ, Oyer R, Johnson GL, Roos D (2000) Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 9:4654–4659CrossRefGoogle Scholar
  12. Ando S, Kaibuchi K, Sasaki T, Hiraoka K, Nishiyama T, Mizuno T, Asada M, Nunoi H, Matsuda I, Matsuura Y, Polakis P, McCormick F, Takai Y (1992) Post-translational processing of rac p21 s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase. J Biol Chem 267:25709–25713PubMedGoogle Scholar
  13. Babior BM (1999) NADPH oxidase: an update. Blood 93:1464–1476PubMedGoogle Scholar
  14. Babior BM, Lambeth JD, Nauseef W (2002) The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342–344CrossRefPubMedGoogle Scholar
  15. Badwey JA, Curnutte JT, Robinson JM, Lazdins JK, Briggs RT, Karnovsky MJ, Karnovsky ML (1980) Comparative aspects of oxidative metabolism of neutrophils from human blood and guinea pig peritonea: magnitude of the respiratory burst, dependence upon stimulating agents, and localization of the oxidases. J Cell Physiol 105:541–551PubMedGoogle Scholar
  16. Baehner RL, Nathan DG (1967) Leukocyte oxidase: defective activity in chronic granulomatous disease. Science 155:835–836PubMedGoogle Scholar
  17. Baehner RL, Nathan DG (1968) Quantitative nitro blue tetrazolium test in chronic granulomatous disease. N Engl J Med 278:971–976PubMedGoogle Scholar
  18. Baldridge C, Gerard R (1933) The extra respiration of phagocytosis. Am J Physiol 103:235–236Google Scholar
  19. Baumeister W, Walz J, Zuhl F, Seemuller E (1998) The proteasome: paradigm of a self-compartmentalizing protease. Cell 92:367–380CrossRefPubMedGoogle Scholar
  20. Berthier S, Paclet MH, Lerouge S, Roux F, Vergnaud S, Coleman AW, Morel F (2003) Changing the conformation state of cytochrome b558 initiates NADPH oxidase activation. J Biol Chem 278:25499–25508CrossRefPubMedGoogle Scholar
  21. Biberstine-Kinkade KJ, Yu L, Dinauer MC (1999) Mutagenesis of an arginine- and lysine-rich domain in the gp91phox subunit of the phagocyte NADPH-oxidase flavocytochrome b558. J Biol Chem 274:10451–10457CrossRefPubMedGoogle Scholar
  22. Bokoch GM, Diebold BA (2002) Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 100:2692–2696CrossRefPubMedGoogle Scholar
  23. Bokoch GM, Bohl BP, Chuang T-H (1994) Guanine nucleotide exchange regulates membrane translocation of Rac/Rho GTP-binding proteins. J Biol Chem 269:31674–31679PubMedGoogle Scholar
  24. Borregaard N, Tauber AI (1984) Subcellular localization of the human neutrophil NADPH oxidase: b-cytochrome and associated flavoprotein. J Biol Chem 259:47–52PubMedGoogle Scholar
  25. Borregaard N, Heiple JM, Simons ER, Clark RA (1983) Subcellular localization of the b-cytochrome component of the human neutrophil microbicidal oxidase: translocation during activation. J Cell Biol 97:52–61CrossRefPubMedGoogle Scholar
  26. Bridges RA, Berendes H, Good RA (1959) A fatal granulomatous disease of childhood. Am J Dis Child 97:387–408Google Scholar
  27. Bromberg Y, Pick E (1985) Activation of NADPH-dependent superoxide production in a cell-free system by sodium dodecyl sulfate. J Biol Chem 260:13539–13545PubMedGoogle Scholar
  28. Brown GE, Stewart MQ, Liu H, Ha VL, Yaffe MB (2003) A novel assay system implicates PtdIns(3,4)P2, PtdIns(3)P, and PKCd in intracellular production of reactive oxygen species by the NADPH oxidase. Mol Cell 11:35–47CrossRefPubMedGoogle Scholar
  29. Burritt JB, Quinn MT, Jutila MA, Bond CW, Doss KW, Jesaitis AJ (1994) Random sequence peptide library analysis of neutrophil flavocytochrome B structure (abstract). Mol Biol Cell 5:121aGoogle Scholar
  30. Burritt JB, Quinn MT, Bond CW, Bond CW, Jesaitis AJ (1995) Topological mapping of neutrophil cytochrome b with phage display. J Biol Chem 270:16974–16980CrossRefPubMedGoogle Scholar
  31. Burritt JB, Busse SC, Gizachew D, Siemsen DW, Quinn MT, Bond CW, Dratz EA, Jesaitis AJ (1998) Antibody imprint of a membrane protein surface. J Biol Chem 273:24847–24852CrossRefPubMedGoogle Scholar
  32. Burritt JB, DeLeo FR, McDonald CL, Prigge JR, Dinauer MC, Nakamura M, Nauseef WM, Jesaitis AJ (2001) Phage display epitope mapping of human neutrophil flavocytochrome b558. J Biol Chem 276:2053–2061CrossRefPubMedGoogle Scholar
  33. Burritt JB, Foubert TR, Baniulis D, Lord CI, Taylor RM, Mills JS, Baughan TD, Roos D, Parkos CA, Jesaitis AJ (2003) Functional epitope on human neutrophil flavocytochrome b558. J Immunol 170:6082–6089PubMedGoogle Scholar
  34. Chittenden T, Harrington EA, O’Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (1995) Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374:733–736CrossRefPubMedGoogle Scholar
  35. Clark RA, Leidal KG, Pearson DW, Nauseef WM (1987) NADPH oxidase of human neutrophils: subcellular localization and characterization of an arachidonate-activatable superoxide-generating system. J Biol Chem 262:4065–4074PubMedGoogle Scholar
  36. Cross A (2000) p40phox participates in the activation of NADPH oxidase by increasing the affinity of p47phox for flavocytochrome b558. Biochem J 349:113–117CrossRefPubMedGoogle Scholar
  37. Cross AR, Erickson RW, Curnutte JT (1999) The mechanism of activation of NADPH oxidase in the cell-free system: the activation process is primarily catalytic and not through the formation of a stoichiometric complex. Biochem J 341:251–255CrossRefPubMedGoogle Scholar
  38. Cross AR, Noack D, Rae J, Curnutte JT, Heyworth PG (2000) Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update). Blood Cells Mol Dis 26:561–565CrossRefPubMedGoogle Scholar
  39. Curnutte JT (1985) Activation of human neutrophil nicotinamide adenine dinucleotide phosphate, reduced (triphosphopyridine nucleotide, reduced) oxidase by arachidonic acid in a cell-free system. J Clin Invest 75:1740–1743PubMedGoogle Scholar
  40. Dang P, Cross A, Babior B (2001) Assembly of the neutrophil respiratory burst oxidase: a direct interaction between p67phox and cytochrome b558. Proc Natl Acad Sci U S A 98:3001–3005CrossRefPubMedGoogle Scholar
  41. Dang PM-C, Cross AR, Quinn MT, Babior BM (2002) Assembly of the neutrophil respiratory burst oxidase: a direct interaction between p67PHOX and cytochrome b558 II. Proc Natl Acad Sci U S A 99:4262–4265CrossRefPubMedGoogle Scholar
  42. Dang PMC, Morel F, Gougerot-Pocidalo MA, El Benna J (2003) Phosphorylation of the NADPH oxidase component p67PHOX by ERK2 and P38MAPK: selectivity of phosphorylated sites and existence of an intramolecular regulatory domain in the tetratricopeptide-rich region. Biochemistry 42:4520–4526CrossRefPubMedGoogle Scholar
  43. Das AK, Cohen PTW, Barford D (1998) The structure of the tetratricopeptide repeats of protein phosphatase 5: implications for TPR-mediated protein–protein interactions. EMBO J 17:1192–1199CrossRefPubMedGoogle Scholar
  44. DeLeo FR, Quinn MT (1996) Assembly of the phagocyte NADPH oxidase: molecular interactions of oxidase proteins. J Leukoc Biol 60:677–691PubMedGoogle Scholar
  45. DeLeo FR, Nauseef WM, Jesaitis AJ, Burritt JB, Clark RA, Quinn MT (1995a) A domain of p47phox that interacts with human neutrophil flavocytochrome b558. J Biol Chem 270:26246–26251CrossRefPubMedGoogle Scholar
  46. DeLeo FR, Yu L, Burritt JB, Loetterle LR, Bond CW, Jesaitis AJ, Quinn MT (1995b) Mapping sites of interaction of p47-phox and flavocytochrome b with random-sequence peptide phage display libraries. Proc Natl Acad Sci U S A 92:7110–7114PubMedGoogle Scholar
  47. DeLeo FR, Allen L-AH, Apicella MA, Nauseef WM (1999) NADPH oxidase activation and assembly during phagocytosis. J Immunol 163:6732–6740PubMedGoogle Scholar
  48. de Mendez I, Adams AG, Sokolic RA, Malech HL, Leto TL (1996) Multiple SH3 domain interactions regulate NADPH oxidase assembly in whole cells. EMBO J 15:1211–1220PubMedGoogle Scholar
  49. de Mendez I, Homayounpour N, Leto TL (1997) Specificity of p47phox SH3 domain interactions in NADPH oxidase assembly and activation. Mol Cell Biol 17:2177–2184PubMedGoogle Scholar
  50. Dibbert B, Weber M, Nikolaizik WH, Vogt P, Schöni MH, Blaser K, Simon HU (1999) Cytokine-mediated bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation. Proc Natl Acad Sci U S A 96:13330–13335CrossRefPubMedGoogle Scholar
  51. Diebold B, Bokoch G (2001) Molecular basis for Rac2 regulation of phagocytic NADPH oxidase. Nat Immunol 2:211–215CrossRefPubMedGoogle Scholar
  52. Diekmann D, Abo A, Johnston C, Segal AW, Hall A (1994) Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Science 265:531–534PubMedGoogle Scholar
  53. Diekmann D, Nobes CD, Burbelo PD, Abo A, Hall A (1995) Rac GTPase interacts with GAPs and target proteins through multiple effector sites. EMBO J 14:5297–5305PubMedGoogle Scholar
  54. Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA (1987) The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327:717–720CrossRefPubMedGoogle Scholar
  55. Dinauer MC, Nauseef WM, Newburger PE (2001) Inherited disorders of phagocyte killing. In: Scriver CR, Beaudet, Valle D, Sly WS, Childs B, Kinzler KW, Vogelstein B (eds) The metabolic and molecular bases of inherited diseases. McGraw-Hill, New York, pp 4857–4887Google Scholar
  56. Dorseuil O, Quinn MT, Bokoch GM (1995) Dissociation of Rac translocation from p47phox/p67phox movements in human neutrophils by tyrosine kinase inhibitors. J Leukoc Biol 58:108–113PubMedGoogle Scholar
  57. Doussiere J, Bouzidi F, Vignais PV (2002) The S100A8/A9 protein as a partner for the cytosolic factors of NADPH oxidase activation in neutrophils. Eur J Biochem 269:3246–3255CrossRefPubMedGoogle Scholar
  58. Downing JF, Pasula R, Wright JR, Twigg HL III, Martin WJ II (1995) Surfactant protein A promotes attachment of Mycobacterium tuberculosis to alveolar macrophages during infection with human immunodeficiency virus. Proc Natl Acad Sci U S A 92:4848–4852PubMedGoogle Scholar
  59. Dusi S, Rossi F (1993) Activation of NADPH oxidase of human neutrophils involves the phosphorylation and the translocation of cytosolic p67phox. Biochem J 296:367–371PubMedGoogle Scholar
  60. Dusi S, Donini M, Rossi F (1996) Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2 from the cytosol to the membranes in human neutrophils lacking p47phox or p67phox. Biochem J 314:409–412PubMedGoogle Scholar
  61. Dusi S, Nadalini KA, Donini M, Zentilin L, Wientjes FB, Roos D, Giacca M, Rossi F (1998) Nicotinamide-adenine dinucleotide phosphate oxidase assembly and activation in EBV-transformed B lymphoblastoid cell lines of normal and chronic granulomatous disease patients. J Immunol 161:4968–4974PubMedGoogle Scholar
  62. Ebisu K, Nagasawa T, Watanabe K, Kakinuma K, Miyano K, Tamura M (2001) Fused p47phox and p67phox truncations efficiently reconstitute NADPH oxidase with higher activity and stability than the individual components. J Biol Chem 276:24498–24505CrossRefPubMedGoogle Scholar
  63. El Benna J, Dang PMC, Gaudry M, Fay M, Morel F, Hakim J, Gougerot-Pocidalo M-A (1997) Phosphorylation of the respiratory burst oxidase subunit p67phox during human neutrophil activation. J Biol Chem 272:17204–17208CrossRefPubMedGoogle Scholar
  64. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635CrossRefPubMedGoogle Scholar
  65. Forbes LV, Moss SJ, Segal AW (1999a) Phosphorylation of p67phox in the neutrophil occurs in the cytosol and is independent of p47phox. FEBS Lett 449:225–229Google Scholar
  66. Forbes LV, Truong O, Wientjes FB, Moss SJ, Segal AW (1999b) The major phosphorylation site of the NADPH oxidase component p67phox is Thr233. Biochem J 338:99–105CrossRefPubMedGoogle Scholar
  67. Foubert TR, Burritt JB, Taylor RM, Jesaitis AJ (2002) Structural changes are induced in human neutrophil cytochrome b by NADPH oxidase activators, LDS, SDS, and arachidonate: intermolecular resonance energy transfer between trisulfopyrenyl-wheat germ agglutinin and cytochrome b558. Biochim Biophys Acta 78380:1–11Google Scholar
  68. Freeman JL, Abo A, Lambeth JD (1996) Rac “insert region” is a novel effector region that is implicated in the activation of NADPH oxidase, but not PAK65. J Biol Chem 271:19794–19801CrossRefPubMedGoogle Scholar
  69. Grizot S, Fieschi F, Dagher M-C, Pebay-Peyroula E (2001a) The active N-terminal region of p67phox. J Biol Chem 276:21627–21631CrossRefPubMedGoogle Scholar
  70. Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E (2001b) Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox. Biochemistry 40:3127–3133CrossRefPubMedGoogle Scholar
  71. Groemping Y, Lapouge K, Smerdon SJ, Rittinger K (2003) Molecular basis of phosphorylation-induced activation of the NADPH oxidase. Cell 113:343–355CrossRefPubMedGoogle Scholar
  72. Hampton MB, Kettle AJ, Winterbourn CC (1998) Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 92:3007–3017PubMedGoogle Scholar
  73. Han C-H, Freeman JLR, Lee T, Motalebi SA, Lambeth JD (1998) Regulation of the neutrophil respiratory oxidase. J Biol Chem 273:16663–16668CrossRefPubMedGoogle Scholar
  74. Hata K, Takeshige K, Sumimoto H (1997) Roles for proline-rich regions of p47phox and p67phox in the phagocyte NADPH oxidase activation in vitro. Biochem Biophys Res Commun 241:226–231CrossRefPubMedGoogle Scholar
  75. Hata K, Ito T, Takeshige K, Sumimoto H (1998) Anionic amphiphile-independent activation of the phagocyte NADPH oxidase in a cell-free system by p47phox both in C-terminally truncated forms. J Biol Chem 273:4232–4236CrossRefPubMedGoogle Scholar
  76. Heller T, Gessner JE, Schmidt RE, Klos A, Bautsch W, Kohl J (1999) Cutting edge: Fc receptor type I for IgG on macrophages and complement mediate the inflammatory response in immune complex peritonitis. J Immunol 162:5657–5661PubMedGoogle Scholar
  77. Heyneman RA, Vercauteren RE (1984) Activation of an NADPH-dependent oxidase from horse polymorphonuclear leukocytes in a cell-free system. J Leukoc Biol 36:751–759PubMedGoogle Scholar
  78. Heyworth PG, Curnutte JT, Nauseef WM, Volpp BD, Pearson DW, Rosen H, Clark RA (1991a) Neutrophil NADPH oxidase assembly. Membrane translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558. J Clin Invest 87:352–356PubMedGoogle Scholar
  79. Heyworth PG, Curnutte JT, Nauseef WM, Volpp BD, Pearson DW, Rosen H, Clark RA (1991b) Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558. J Clin Invest 87:352–356PubMedGoogle Scholar
  80. Heyworth PG, Knaus UG, Settleman J, Curnutte JT, Bokoch GM (1993) Regulation of NADPH oxidase activity by Rac GTPase activating protein(s). Mol Biol Cell 4:1217–1223PubMedGoogle Scholar
  81. Heyworth PG, Bohl BP, Bokoch GM, Curnutte JT (1994) Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558. J Biol Chem 269:30749–30752PubMedGoogle Scholar
  82. Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 15:578–584CrossRefPubMedGoogle Scholar
  83. Hiroaki H, Ago T, Ito T, Sumimoto H, Kohda D (2001) Solution structure of the PX domain, a target of the SH3 domain. Nat Struct Biol 8:526–530CrossRefPubMedGoogle Scholar
  84. Hoffmann GR, Nassar N, Cerione RA (2000) Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100:345–356CrossRefPubMedGoogle Scholar
  85. Holmes B, Quie P, Windhorst D, Good R (1966) Fatal granulomatous disease of childhood. Lancet 1:1225–1228CrossRefPubMedGoogle Scholar
  86. Holmes B, Page AR, Good RA (1967) Studies of the metabolic activity of leukocytes from patients with a genetic abnormality of phagocytic function. J Clin Invest 46:1422–1432PubMedGoogle Scholar
  87. Hoyal CR, Gutierrez A, Young BM, Catz SD, Lin JH, Tsichlis PN, Babior BM (2003) Modulation of p47phox activity by site-specific phosphorylation: akt-dependent activation of the NADPH oxidase. Proc Natl Acad Sci U S A 100:5130–5135CrossRefPubMedGoogle Scholar
  88. Inanami O, Johnson JL, McAdara JK, El Benna J, Faust LRP, Newburger PE, Babior BM (1998) Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphorylation of p47PHOX on serine 303 or 304. J Biol Chem 273:9539–9543CrossRefPubMedGoogle Scholar
  89. Ito T, Matsui Y, Ago T, Ota K, Sumimoto H (2001) Novel modular domain PB1 recognizes PC motif to mediate functional protein–protein interactions. EMBO J 20:1–9CrossRefPubMedGoogle Scholar
  90. Iyer GYN, Islam DMF, Quastel JH (1961) Biochemical aspects of phagocytosis. Nature 192:535–541Google Scholar
  91. Iyer SS, Pearson DW, Nauseef WM, Clark RA (1994) Evidence for a readily dissociable complex of p47phox and p67phox in cytosol of unstimulated human neutrophils. J Biol Chem 269:22405–22411PubMedGoogle Scholar
  92. Jandl RC, Andre-Schwartz J, Borges-DuBois L, Kipnes RS, McMurrich BJ, Babior BM (1978) Termination of the respiratory burst in human neutrophils. J Clin Invest 61:1176–1185PubMedGoogle Scholar
  93. Johnson JL, Park J-W, El Benna J, Faust LP, Inanami O, Babior BM (1998) Activation of p47phox, a cytosolic subunit of the leukocyte NADPH oxidase. J Biol Chem 273:35147–35152CrossRefPubMedGoogle Scholar
  94. Johnston RB Jr, McMurry J (1967) Chronic granulomatous disease: a report of five cases and a review of the literature. Am J Dis Child 114:370–379PubMedGoogle Scholar
  95. Kami K, Takeya R, Sumimoto H, Kohda D (2002) Diverse recognition of non-PXXP peptide ligands by the SH3 domains from p67phox, Grb2 and Pex13p. EMBO J 21:4268–4276CrossRefPubMedGoogle Scholar
  96. Kanai F, Liu H, Field S, Akbary H, Matsuo T, Brown G, Cantley L, Yaffe M (2000) The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat Cell Biol 3:675–678CrossRefGoogle Scholar
  97. Karathanassis D, Stahelin RV, Bravo J, Perisic O, Pacold CM, Cho WW, Williams RL (2002) Binding of the PX domain of p47phox to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction. EMBO J 21:5057–5068CrossRefPubMedGoogle Scholar
  98. Karlsson A, Dahlgren C (2002) Assembly and activation of the neutrophil NADPH oxidase in granule membranes. Antioxid Redox Signal 4:49–60CrossRefPubMedGoogle Scholar
  99. Klebanoff SJ (1970) Myeloperoxidase: contribution to the microbicidal activity of intact leukocytes. Science 169:1095–1097PubMedGoogle Scholar
  100. Kleinberg ME, Malech HL, Mital DA, Leto TL (1994) p21rac does not participate in the early interaction between p47-phox and cytochrome b558 that leads to phagocyte NADPH oxidase activation in vitro. Biochemistry 33:2490–2495PubMedGoogle Scholar
  101. Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM (1991) Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science 254:1512–1515PubMedGoogle Scholar
  102. Knaus UG, Heyworth PG, Kinsella BT, Curnutte JT, Bokoch GM (1992) Purification and characterization of Rac 2. J Biol Chem 267:23575–23582PubMedGoogle Scholar
  103. Kobayashi T, Robinson JM, Seguchi H (1998) Identification of intracellular sites of superoxide production in stimulated neutrophils. J Cell Sci 111:81–91PubMedGoogle Scholar
  104. Koga H, Terasawa H, Nunoi H, Takeshige K, Inagaki F, Sumimoto H (1999) Tetratricopeptide repeat (TPR) motifs of p67phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. J Biol Chem 274:25051–25060CrossRefPubMedGoogle Scholar
  105. Kreck ML, Freeman JL, Abo A, Lambeth JD (1996) Membrane association of Rac is required for high activity of the respiratory burst oxidase. Biochemistry 35:15683–15692CrossRefPubMedGoogle Scholar
  106. Kuribayashi F, Nunoi H, Wakamatsu K, Tsunawaki S, Sato K, Ito T, Sumimoto H (2002) The adaptor protein p40phox as a positive regulator of the superoxide-producing phagocyte oxidase. EMBO J 21:6312–6320CrossRefPubMedGoogle Scholar
  107. Kurkchubasche AG, Panepinto JA, Tracy TR, Thurman GW, Ambruso DR (2001) Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease. J Pediatr 139:141–147CrossRefPubMedGoogle Scholar
  108. Kwong CH, Adams AG, Leto TL (1995) Characterization of the effector-specifying domain of Rac involved in NADPH oxidase activation. J Biol Chem 270:19868–19872CrossRefPubMedGoogle Scholar
  109. Lambeth J (2000) Regulation of the phagocyte respiratory burst oxidase by protein interactions. J Biochem Mol Biol 33:427–439Google Scholar
  110. Lang ML, Kerr MA (2000) Neutrophil NADPH oxidase does not assemble on macropinocytic vacuole membranes. Immunol Lett 72:1–6CrossRefPubMedGoogle Scholar
  111. Lapouge K, Smith SJM, Walker PA, Gamblin SJ, Smerdon SJ, Rittinger K (2000) Structure of the TPR domain of p67phox in complex with Rac-GTP. Mol Cell 6:899–907PubMedGoogle Scholar
  112. Lapouge K, Smith SJM, Groemping Y, Rittinger K (2002) Architecture of the p40-p47-p67phox complex in the resting state of the NADPH oxidase. J Biol Chem 277:10121–10128CrossRefPubMedGoogle Scholar
  113. Le A, Steiner JL, Ferrell GA, Shaker JC, Sifers RN (1994) Association between calnexin and a secretion-incompetent variant of human a1-antitrypsin. J Biol Chem 269:7514–7519PubMedGoogle Scholar
  114. Le Cabec V, Möhn H, Gacon G, Maridonneau-Parini I (1994) The small GTP-binding protein rac is not recruited to the plasma membrane upon NADPH oxidase activation in human neutrophils. Biochem Biophys Res Commun 198:1216–1224CrossRefPubMedGoogle Scholar
  115. Lekstrom-Himes J, Gallin J (2000) Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 343:1703–1714CrossRefPubMedGoogle Scholar
  116. Leto TL, Lomax KJ, Volpp BD, Nunoi H, Sechler JMG, Nauseef WM, Clark RA, Gallin JI, Malech HL (1990) Cloning of a 67 K neutrophil cytosolic factor and its similarity to a noncatalytic region of p60c-src. Science 248:727–730PubMedGoogle Scholar
  117. Leusen JHW, Bolscher BGJM, Hilarius PM, Weening RS, Kaulfersch W, Seger RA, Roos D, Verhoeven AJ (1994a) 156Pro–Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox. J Exp Med 180:2329–2334CrossRefPubMedGoogle Scholar
  118. Leusen JHW, De Boer M, Bolscher BGJM, Hilarius PM, Weening RS, Ochs HD, Roos D, Verhoeven AJ (1994b) A point mutation in gp91-phox of cytochrome b558 of the human NADPH oxidase leading to defective translocation of the cytosolic proteins p47-phox and p67-phox. J Clin Invest 93:2120–2126PubMedGoogle Scholar
  119. Leusen JHW, De Klein A, Hilarius PM, Ahlin A, Palmblad J, Smith CIE, Diekmann D, Hall A, Verhoeven AJ, Roos D (1996) Distrubed interaction of p21-rac with mutated p67-phox causes chronic granulomatous disease. J Exp Med 184:1243–1249CrossRefPubMedGoogle Scholar
  120. Leusen JHW, Eppink MHM, Hilarius PM, De Boer M, Weening RS, Ahlin A, Sanders L, Goldblatt D, Skopczynska H, Bernatowska E, Palmblad J, Verhoeven AJ, van Berkel WJH, Roos D (2000) Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly. Blood 95:666–673PubMedGoogle Scholar
  121. Maly FE, Schuerer-Maly CC, Quilliam L, Cochrane CG, Newburger PE, Curnutte JT, Gifford M, Dinauer MC (1993) Restitution of superoxide generation in autosomal cytochrome-negative chronic granulomatous disease (A220 CGD)-derived B lymphocyte cell lines by transfection with p22phox cDNA. J Exp Med 178:2047–2053CrossRefPubMedGoogle Scholar
  122. McPhail LC, Shirley PS, Clayton CC, Snyderman R (1985) Activation of the respiratory burst enzyme from human neutrophils in a cell-free system: evidence for a soluble cofactor. J Clin Invest 75:1735–1739PubMedGoogle Scholar
  123. Miyano K, Ogasawara S, Han CH, Fukuda H, Tamura M (2001) A fusion protein between Rac and p67phox (1–210) reconstitutes NADPH oxidase with higher activity and stability than the individual components. Biochemistry 40:14089–14097CrossRefPubMedGoogle Scholar
  124. Miyano K, Fukuda H, Ebisu K, Tamura M (2003) Remarkable stabilization of neutrophil NADPH oxidase using RacQ61L and a P67phox-p47phox fusion protein. Biochemistry 42:184–190CrossRefPubMedGoogle Scholar
  125. Mizuno T, Kaibuchi K, Ando S, Musha T, Hiraoka K, Takaishi K, Asada M, Nunoi H, Matsuda I, Takai Y (1992) Regulation of the superoxide-generating NADPH oxidase by a small GTP-binding protein and its stimulatory and inhibitory GDP/GTP exchange proteins. J Biol Chem 267:10215–10218PubMedGoogle Scholar
  126. Morozov I, Lotan O, Joseph G, Gorzalczany Y, Pick E (1998) Mapping of functional domains in p47phox involved in the activation of NADPH oxidase by “peptide walking”. J Biol Chem 273:15435–15444CrossRefPubMedGoogle Scholar
  127. Moser B, Schumacher C, Von Tscharner V, Clark-Lewis I, Baggiolini M (1991) Neutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils. J Biol Chem 266:10666–10671PubMedGoogle Scholar
  128. Nagasawa T, Ebisu K, Inoue Y, Miyano K, Tamura M (2003) A new role of Pro-73 of p47phox in the activation of neutrophil NADPH oxidase. Arch Biochem Biophys 416:92–100CrossRefPubMedGoogle Scholar
  129. Nakamura R, Sumimoto H, Mizuki K, Hata K, Ago T, Kitajima S, Takehige K, Sakaki Y, Ito T (1998) The PC motif: a novel and evolutionarily conserved sequence involved in interaction between p40phox and p67phox, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase. Eur J Biochem 251:583–589CrossRefPubMedGoogle Scholar
  130. Nathan C (2003) Oxygen and the inflammatory cell. Nature 422:675–676CrossRefPubMedGoogle Scholar
  131. Nauseef WM (1999) The NADPH-dependent oxidase of phagocytes. Proc Assoc Am Phys 111:373–382Google Scholar
  132. Nauseef WM, Metcalf JA, Root RK (1983) Role of myeloperoxidase in the respiratory burst of human neutrophils. Blood 61:483–491PubMedGoogle Scholar
  133. Nauseef WM, McCormick S, Renee J, Leidal KG, Clark RA (1993) Functional domain in an arginine-rich carboxy terminal region of p47 phox. J Biol Chem 268:23646–23651PubMedGoogle Scholar
  134. Nisimoto Y, Freeman JLR, Motalebi SZ, Hirshberg M, Lambeth JD (1997) Rac binding to p67phox. J Biol Chem 272:18834–18841CrossRefPubMedGoogle Scholar
  135. Nisimoto Y, Motalebi S, Han CH, Lambeth JD (1999) The p67phox activation domain regulates electron flow from NADPH to flavin in flavocytochrome b558. J Biol Chem 274:22999–23005CrossRefPubMedGoogle Scholar
  136. Nunoi H, Rotrosen D, Gallin JI, Malech HL (1988) Two forms of autosomal chronic granulomatous disease lack distinct neutrophil cytosol factors. Science 242:1298–1301PubMedGoogle Scholar
  137. Ohno Y-I, Hirai K-I, Kanoh T, Uchino H, Ogawa K (1982a) Subcellular localization of H2O2 production in human neutrophils stimulated with particles and an effect of cytochalasin-B on cells. Blood 60:253–260PubMedGoogle Scholar
  138. Ohno Y-I, Hirai K-I, Kanoh T, Uchino H, Ogawa K (1982b) Subcellular localization of hydrogen peroxide production in human polymorphonuclear leukocytes stimulated with lectins, phorbol myristate acetate, and digitonin: an electron microscopic study using CeCl3. Blood 60:1195–1202PubMedGoogle Scholar
  139. Oldenborg P, Zheleznyak A, Fang Y, Lagenaur C, Gresham H, Lindberg F (2000) Role of CD47 as a marker of self on red blood cells. Science 288:2051–2054CrossRefPubMedGoogle Scholar
  140. Paclet MH, Coleman AW, Vergnaud S, Morel F (2000) p67-phox-mediated NADPH oxidase assembly: imaging of cytochrome b558 liposomes by atomic force microscopy. Biochemistry 39:9302–9310CrossRefPubMedGoogle Scholar
  141. Park J-W, Ma M, Ruedi JM, Smith RM, Babior BM (1992) The cytosolic components of the respiratory burst oxidase exist as a Mr−240,000 complex that acquires a membrane-binding site during activation of the oxidase in a cell-free system. J Biol Chem 267:17327–17332PubMedGoogle Scholar
  142. Park MY, Imajoh-Ohmi S, Nunoi H, Kanegasaki S (1997) Synthetic peptides corresponding to various hydrophilic regions of the large subunit of cytochrome b558 inhibit superoxide generation in a cell-free system from neutrophils. Biochem Biophys Res Commun 234:531–536CrossRefPubMedGoogle Scholar
  143. Parkos CA, Dinauer MC, Walker LE, Allen RA, Jesaitis AJ, Orkin SH (1988) Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b. Proc Natl Acad Sci U S A 85:3319–3323PubMedGoogle Scholar
  144. Peng GH, Huang J, Boyd M, Kleinberg ME (2003) Properties of phagocyte NADPH oxidase p47-phox mutants with unmasked SH3 (Src homology 3) domains: full reconstitution of oxidase activity in a semi-recombinant cell-free system lacking arachidonic acid. Biochem J 373:221–229CrossRefPubMedGoogle Scholar
  145. Philips MR, Feoktistov A, Pillinger MH, Abramson SB (1995) Translocation of p21rac2 from cytosol to plasma membrane is neither necessary nor sufficient for neutrophil NADPH oxidase activity. J Biol Chem 270:11514–11521CrossRefPubMedGoogle Scholar
  146. Ponting CP (1996) Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains. Protein Sci 5:2353–2357PubMedGoogle Scholar
  147. Proctor RA (2000) Toward an understanding of biomaterial infections: a complex interplay between the host and bacteria. J Lab Clin Med 135:14–15PubMedGoogle Scholar
  148. Quie PG (1993) Chronic granulomatous disease of childhood: a saga of discovery and understanding. Pediatr Infect Dis J 12:395–398PubMedGoogle Scholar
  149. Quie PG, White JG, Holmes B, Good RA (1967) In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest 46:668–679PubMedGoogle Scholar
  150. Quinn MT, Evans T, Loetterle LR, Jesaitis AJ, Bokoch GM (1993) Translocation of Rac correlates with NADPH oxidase activation. Evidence for equimolar translocation of oxidase components. J Biol Chem 268:20983–20987PubMedGoogle Scholar
  151. Regelmann W, Hays N, Quie PG (1983) Chronic granulomatous disease: historical perspective and clinical experience at the University of Minnesota hospitals. In: Gallin JI, Fauci AS (eds) Chronic granulomatous disease. Raven, New York, pp 3–23Google Scholar
  152. Rosen H, Klebanoff SJ (1976) Chemiluminescence and superoxide production by myeloperoxidase-deficient leukocytes. J Clin Invest 58:50–60PubMedGoogle Scholar
  153. Sarfstein R, Gorzalczany Y, Mizrahi A, Berdichevsky Y, Molshanski-Mor S, Weinbaum C, Hirshberg M, Dagher M-C, Pick E (2004) Dual role of Rac in the assembly of the NADPH oxidase, tethering to the membrane and activation of p67phox: a study based on mutagenesis of p67phox-Rac1 chimeras. J Biol Chem 279:16007–16016CrossRefPubMedGoogle Scholar
  154. Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (1997) p40phox down-regulates NADPH oxidase activity through interactions with its SH3 domain. J Biol Chem 272:9141–9146CrossRefPubMedGoogle Scholar
  155. Sbarra AJ, Karnovsky ML (1959) The biochemical basis of phagocytosis. I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes. J Biol Chem 234:1355–1362PubMedGoogle Scholar
  156. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ (2003) BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300:135–139CrossRefPubMedGoogle Scholar
  157. Segal AW, Jones OTG (1978) Novel cytochrome b system in phagocytic vacuoles of human granulocytes. Nature 276:515–517PubMedGoogle Scholar
  158. Shiose A, Sumimoto H (2000) Arachidonic acid and phosphorylation synergistically induce a conformational change of p47phox to activate the phagocyte NADPH oxidase. J Biol Chem 275:13793–13801CrossRefPubMedGoogle Scholar
  159. Shmelzer Z, Haddad N, Admon E, Pessach I, Leto TL, Eitan-Hazan Z, Hershfinkel M, Levy R (2003) Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes. J Cell Biol 162:683–692CrossRefPubMedGoogle Scholar
  160. Someya A, Nagaoka I, Yamashita T (1993) Purification of the 260 kDa cytosolic complex involved in the superoxide production of guinea pig neutrophils. FEBS Lett 330:215–218CrossRefPubMedGoogle Scholar
  161. Stasia MJ, Lardy B, Maturana A, Rousseau P, Martel C, Bordigoni P, Dernaurex N, Morel F (2002) Molecular and functional characterization of a new X-linked chronic granulomatous disease variant (X91+) case with a double missense mutation in the cytosolic gp91phox C-terminal tail. Biochim Biophys Acta Mol Basis Dis 1586:316–330CrossRefGoogle Scholar
  162. Sumimoto H, Ito T, Hata K, Mizuki K, Nakamura R, Kage Y, Sakaki Y, Nakamura M, Takeshige K (1997) Membrane translocation of cytosolic factors in activation of the phagocyte NADPH oxidase: role of protein–protein interactions. In: Hamasaki N, Mihara K (eds) International Symposium Membrane Proteins Structure, Function and Expression Control. Kyushu University Press, Kyushu, pp 235–245Google Scholar
  163. Swain SD, Helgerson SL, Davis AR, Nelson LK, Quinn MT (1997) Analysis of activation-induced conformational changes in p47phox using tryptophan fluorescence spectroscopy. J Biol Chem 272:29502–29510CrossRefPubMedGoogle Scholar
  164. Taylor WR, Jones DT, Segal AW (1993) A structural model for the nucleotide binding domains of the flavocytochrome b-245 b-chain. Protein Sci 2:1675–1685PubMedGoogle Scholar
  165. Toporik A, Gorzalczany Y, Hirshberg M, Pick E, Lotan O (1998) Mutational analysis of novel effector domains in rac1 involved in the activation of nicotinamide adenine dinucleotide phosphate (reduced) oxidase. Biochemistry 37:7147–7156CrossRefPubMedGoogle Scholar
  166. Uhlinger DJ, Burnham DN, Lambeth JD (1991) Nucleoside triphosphate requirements for superoxide generation and phosphorylation in a cell-free system from human neutrophils: sodium dodecyl sulfate and diacylglycerol activate independently of protein kinase C. J Biol Chem 266:20990–20997PubMedGoogle Scholar
  167. van Bruggen R, Anthony E, Fernandez-Borja M, Roos D (2004) Continuous translocation of Rac2 and the NADPH oxidase component p67phox during phagocytosis. J Biol Chem 279:9097–9102CrossRefPubMedGoogle Scholar
  168. Vignais PV (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59:1428–1459CrossRefPubMedGoogle Scholar
  169. Volpp BD, Nauseef WM, Clark RA (1988) Two cytosolic neutrophil NADPH oxidase components absent in autosomal chronic granulomatous disease. Science 242:1295–1298PubMedGoogle Scholar
  170. Wientjes FB, Hsuan JJ, Totty NF, Segal AW (1993) p40phox, a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains. Biochem J 296:557–561PubMedGoogle Scholar
  171. Wientjes FB, Panayotou G, Reeves E, Segal AW (1996) Interactions between cytosolic components of the NADPH oxidase: p40phox interacts with both p67phox and p47phox. Biochem J 317:919–924PubMedGoogle Scholar
  172. Williams DA, Tao W, Yang F, Kim C, Gu Y, Mansfield P, Levine JE, Petryniak B, Derrow CW, Harris C, Jia B, Zheng Y, Ambruso DR, Lowe JB, Atkinson SJ, Dinauer MC, Boxer L (2000) Dominant negative mutation of the hematopoietic-specifc Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96:1646–1654PubMedGoogle Scholar
  173. Wilson L, Butcher C, Finan P, Kellie S (1997) SH3 domain-mediated interactions involving the phox components of the NADPH oxidase. Inflamm Res 46:265–271CrossRefPubMedGoogle Scholar
  174. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H (2000) Chronic granulomatous disease: report on a national registry of 368 patients. Medicine 79:155–169CrossRefPubMedGoogle Scholar
  175. Yaffe MB (2002) The p47phox PX domain: two heads are better than one! Structure 10:1288–1290Google Scholar
  176. Yu L, Dinauer MC (1997) Biosynthesis of the phagocyte NADPH oxidase cytochrome b558. J Biol Chem 272:27288–27294CrossRefPubMedGoogle Scholar
  177. Yu L, Cross AR, Zhen L, Dinauer MC (1999) Functional analysis of NADPH oxidase in granulocytic cells expressing a D488–497 gp91phox deletion mutant. Blood 94:2497–2504PubMedGoogle Scholar
  178. Zhan S, Vazquez N, Wientjes FB, Budarf ML, Schrock E, Ried T, Green ED, Chanock SJ (1998) Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate–oxidase complex. Blood 88:2714–2721Google Scholar
  179. Zhao X, Bey EA, Wientjes FB, Cathcart MK (2002) Cytosolic phospholipase A2 (cPLA2) regulation of human monocyte NADPH oxidase activity. J Biol Chem 277:25385–25392CrossRefPubMedGoogle Scholar
  180. Zhao X, Carnevale KA, Cathcart MK (2003) Human monocytes use rac1, not rac2, in the NADPH oxidase complex. J Biol Chem 278:40788–40792CrossRefPubMedGoogle Scholar
  181. Zhen L, King AAJ, Xiao Y, Chanock SJ, Orkin SH, Dinauer MC (1993) Gene targeting of X chromosome-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. Proc Natl Acad Sci U S A 90:9832–9836PubMedGoogle Scholar

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© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Inflammation Program and Department of Medicine, Roy J. and Lucille A. Carver College of MedicineUniversity of IowaCoralvilleUSA
  2. 2.Department of Veterans AffairsIowa City VA Medical CenterIowa CityUSA

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