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Hydrogen peroxide as second messenger in lymphocyte activation

Nature Immunology volume 3, pages 1129–1134 (2002)Cite this article

Abstract

Oxidants such as H2O2 are connected to lymphocyte activation, but the molecular mechanisms behind this phenomenon are less clear. Here, I review data suggesting that by inhibiting protein tyrosine phosphatases, H2O2 plays an important role as a secondary messenger in the initiation and amplification of signaling at the antigen receptor. These findings explain why exposure of lymphocytes to H2O2 can mimic the effect of antigen. In addition, more recent data show that antigen receptors themselves are H2O2-generating enzymes and that the oxidative burst in macrophages seems to play a role not only in pathogen killing but also in the activation of these as well as neighboring cells. Thus, by controlling the activity of the negative regulatory phosphatases inside the cell, H2O2 can set and influence critical thresholds for lymphocyte activation.

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Figure 1: Regulation of binary intracellular signaling molecules.
Figure 2: Model of the redox regulation of BCR signaling.

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References

  1. Finkel, T. & Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).

    CAS  PubMed  Google Scholar 

  2. Adler, V., Yin, Z., Tew, K.D. & Ronai, Z. Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18, 6104–6111 (1999).

    CAS  PubMed  Google Scholar 

  3. Buttke, T.M. & Sandstrom, P.A. Redox regulation of programmed cell death in lymphocytes. Free Radical Res. 22, 389–397 (1995).

    CAS  Google Scholar 

  4. Roth, S. & Droge, W. Regulation of T-cell activation and T-cell growth factor (TCGF) production by hydrogen peroxide. Cell Immunol. 108, 417–424 (1987).

    CAS  PubMed  Google Scholar 

  5. Staal, F.J., Anderson, M.T., Staal, G.E., Herzenberg, L.A. & Gitler, C. Redox regulation of signal transduction: tyrosine phosphorylation and calcium influx. Proc. Natl. Acad. Sci. USA 91, 3619–3622 (1994).

    CAS  PubMed  Google Scholar 

  6. Bae, Y.S. et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J. Biol. Chem. 272, 217–221 (1997).

    CAS  PubMed  Google Scholar 

  7. Mahadev, K., Zilbering, A., Zhu, L. & Goldstein, B.J. Insulin-stimulated hydrogen peroxide reversibly inhibits protein- tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J. Biol. Chem. 276, 21938–21942 (2001).

    CAS  PubMed  Google Scholar 

  8. Rhee, S.G., Bae, Y.S., Lee, S.R. & Kwon, J. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci. STKE 53, 1–6 (2000).

    Google Scholar 

  9. Gamaley, I.A. & Klyubin, I.V. Roles of reactive oxygen species: signaling and regulation of cellular functions. Int. Rev. Cytol. 188, 203–255 (1999).

    CAS  PubMed  Google Scholar 

  10. Finkel, T. Signal transduction by reactive oxygen species in non-phagocytic cells. J. Leukoc. Biol. 65, 337–340 (1999).

    CAS  PubMed  Google Scholar 

  11. Gulati, P. et al. Redox regulation in mammalian signal transduction. IUBMB Life 52, 25–28 (2001).

    CAS  PubMed  Google Scholar 

  12. Finkel, T. Reactive oxygen species and signal transduction. IUBMB Life 52, 3–6 (2001).

    CAS  PubMed  Google Scholar 

  13. Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).

    CAS  PubMed  Google Scholar 

  14. Bogdan, C. Nitric oxide and the immune response. Nature Immunol. 2, 907–916 (2001).

    CAS  Google Scholar 

  15. Bootman, M.D. et al. Calcium signaling–an overview. Semin. Cell Dev. Biol. 12, 3–10 (2001).

    CAS  PubMed  Google Scholar 

  16. Huyer, G. et al. Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272, 843–851 (1997).

    CAS  PubMed  Google Scholar 

  17. Nordberg, J. & Arner, E.S. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radical Biol. Med. 31, 1287–1312 (2001).

    CAS  Google Scholar 

  18. Sun, Y. & Oberley, L.W. Redox regulation of transcriptional activators. Free Radical Biol. Med. 21, 335–348 (1996).

    CAS  Google Scholar 

  19. Schreck, R., Rieber, P. & Baeuerle, P.A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J. 10, 2247–2258 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Caselli, A. et al. The inactivation mechanism of low molecular weight phosphotyrosine-protein phosphatase by H2O2 . J. Biol. Chem. 273, 32554–32560 (1998).

    CAS  PubMed  Google Scholar 

  21. Xu, D., Rovira, I.I., II & Finkel, T. Oxidants painting the cysteine chapel: redox regulation of PTPs. Dev. Cell 2, 251–252 (2002).

    CAS  PubMed  Google Scholar 

  22. Neel, B.G. & Tonks, N.K. Protein tyrosine phosphatases in signal transduction. Curr. Opin. Cell. Biol. 9, 193–204 (1997).

    CAS  PubMed  Google Scholar 

  23. Andersen, J.N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol. 21, 7117–7136 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Segal, A.W. & Shatwell, K.P. The NADPH oxidase of phagocytic leukocytes. Ann. NY Acad. Sci. 832, 215–222 (1997).

    CAS  PubMed  Google Scholar 

  25. Babior, B.M., Lambeth, J.D. & Nauseef, W. The neutrophil NADPH oxidase. Arch. Biochem. Biophys. 397, 342–344 (2002).

    CAS  PubMed  Google Scholar 

  26. Diebold, B.A. & Bokoch, G.M. Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nature Immunol. 2, 211–215 (2001).

    CAS  Google Scholar 

  27. Reeves, E.P. et al. Direct interaction between p47phox and protein kinase C: evidence for targeting of protein kinase C by p47phox in neutrophils. Biochem. J. 344, 859–866 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tsunawaki, S. & Yoshikawa, K. Relationships of p40phox with p67phox in the activation and expression of the human respiratory burst NADPH oxidase. J. Biochem. (Tokyo) 128, 777–783 (2000).

    CAS  Google Scholar 

  29. Dekaris, I., Marotti, T., Sprong, R.C., van Oirschot, J.F. & van Asbeck, B.S. Hydrogen peroxide modulation of the superoxide anion production by stimulated neutrophils. Immunopharmacol. Immunotoxicol. 20, 103–117 (1998).

    CAS  PubMed  Google Scholar 

  30. Inanami, O. et al. Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphorylation of p47phox on serine 303 or 304. J. Biol. Chem. 273, 9539–9543 (1998).

    CAS  PubMed  Google Scholar 

  31. Verhoeven, A.J. The NADPH oxidase: lessons from chronic granulomatous disease neutrophils. Ann. NY Acad. Sci. 832, 85–92 (1997).

    CAS  PubMed  Google Scholar 

  32. Jackson, S.H., Gallin, J.I. & Holland, S.M. The p47phox mouse knock-out model of chronic granulomatous disease. J. Exp. Med. 182, 751–758 (1995).

    CAS  PubMed  Google Scholar 

  33. Pollock, J.D. et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nature Genet. 9, 202–209 (1995).

    CAS  PubMed  Google Scholar 

  34. Roy, A. et al. Mice lacking in gp91phox subunit of NAD(P)H oxidase showed glomus cell [Ca2+](i) and respiratory responses to hypoxia. Brain Res. 872, 188–193 (2000).

    CAS  PubMed  Google Scholar 

  35. De Deken, X. et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J. Biol. Chem. 275, 23227–23233 (2000).

    CAS  PubMed  Google Scholar 

  36. Lassegue, B. et al. Novel gp91phox homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ. Res. 88, 888–894 (2001).

    CAS  PubMed  Google Scholar 

  37. Sorescu, D. et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105, 1429–1435 (2002).

    CAS  PubMed  Google Scholar 

  38. Cheng, G., Cao, Z., Xu, X., van Meir, E.G. & Lambeth, J.D. Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269, 131–140 (2001).

    CAS  PubMed  Google Scholar 

  39. Yang, S., Madyastha, P., Bingel, S., Ries, W. & Key, L. A new superoxide-generating oxidase in murine osteoclasts. J. Biol. Chem. 276, 5452–5458 (2001).

    CAS  PubMed  Google Scholar 

  40. Devadas, S., Zaritskaya, L., Rhee, S.G., Oberley, L. & Williams, M.S. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J. Exp. Med. 195, 59–70 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Amital, H., Tur-Kaspa, I., Tashma, Z., Hendler, I. & Shoenfeld, Y. Catalytic antibodies. Structure and possible applications. Meth. Mol. Biol. 51, 203–210 (1995).

    CAS  Google Scholar 

  42. Wentworth, P. Jr. & Janda, K.D. Catalytic antibodies: structure and function. Cell Biochem. Biophys. 35, 63–87 (2001).

    CAS  PubMed  Google Scholar 

  43. Wentworth, P. Jr. et al. Antibody catalysis of the oxidation of water. Science 293, 1806–1811 (2001).

    CAS  PubMed  Google Scholar 

  44. Datta, D., Vaidehi, N., Xu, X. & Goddard, W.A. 3rd. Mechanism for antibody catalysis of the oxidation of water by singlet dioxygen. Proc. Natl. Acad. Sci. USA 99, 2636–2641 (2002).

    CAS  PubMed  Google Scholar 

  45. Wentworth, A.D., Jones, L.H., Wentworth, P. Jr., Janda, K.D. & Lerner, R.A. Antibodies have the intrinsic capacity to destroy antigens. Proc. Natl. Acad. Sci. USA 97, 10930–10935 (2000).

    CAS  PubMed  Google Scholar 

  46. Wienands, J., Larbolette, O. & Reth, M. Evidence for a preformed transducer complex organized by the B cell antigen receptor. Proc. Natl. Acad. Sci. USA 93, 7865–7870 (1996).

    CAS  PubMed  Google Scholar 

  47. Barford, D. & Neel, B.G. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure 6, 249–254 (1998).

    CAS  PubMed  Google Scholar 

  48. Weiss, A. & Schlessinger, J. Switching signals on or off by receptor dimerization. Cell 94, 277–280 (1998).

    CAS  PubMed  Google Scholar 

  49. Meng, T.C., Fukada, T. & Tonks, N.K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).

    CAS  PubMed  Google Scholar 

  50. Uckun, F.M. et al. Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death. Proc. Natl. Acad. Sci. USA 89, 9005–9009 (1992).

    CAS  PubMed  Google Scholar 

  51. Schieven, G.L., Kirihara, J.M., Myers, D.E., Ledbetter, J.A. & Uckun, F.M. Reactive oxygen intermediates activate NF-κB in a tyrosine kinase-dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes. Blood 82, 1212–1220 (1993).

    CAS  PubMed  Google Scholar 

  52. Zhang, Y., Wienands, J., Zurn, C. & Reth, M. Induction of the antigen receptor expression on B lymphocytes results in rapid competence for signaling of SLP-65 and Syk. EMBO J. 17, 7304–7310 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kurosaki, T. Molecular dissection of B cell antigen receptor signaling. Bioorg. Medicinal Chem. Lett. 1, 515–527 (1998).

    CAS  Google Scholar 

  54. Schamel, W.W.A. & Reth, M. Monomeric and oligomeric complexes of the B cell antigen receptor. Immunity 13, 5–14 (2000).

    CAS  PubMed  Google Scholar 

  55. Reth, M. Antigen receptor tail clue. Nature 338, 383–384 (1989).

    CAS  PubMed  Google Scholar 

  56. Cambier, J.C. New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). Immunol. Today 16, 110 (1995).

    CAS  PubMed  Google Scholar 

  57. Kurosaki, T. Genetic analysis of B cell antigen receptor signaling. Annu. Rev. Immunol. 17, 555–592 (1999).

    CAS  PubMed  Google Scholar 

  58. Tamir, I., Dal Porto, J.M. & Cambier, J.C. Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction. Curr. Opin. Immunol. 12, 307–315 (2000).

    CAS  PubMed  Google Scholar 

  59. Shiue, L., Zoller, M.J. & Brugge, J.S. Syk is activated by phosphotyrosine-containing peptides representing the tyrosine-based activation motifs of the high affinity receptor for IgE. J. Biol. Chem. 270, 10498–10502 (1995).

    CAS  PubMed  Google Scholar 

  60. Rowley, R.B., Burkhardt, A.L., Chao, H.G., Matsueda, G.R. & Bolen, J.B. Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Igα/Igβ immunoreceptor tyrosine activation motif binding and autophosphorylation. J. Biol. Chem. 270, 11590–11594 (1995).

    CAS  PubMed  Google Scholar 

  61. Futterer, K., Wong, J., Grucza, R.A., Chan, A.C. & Waksman, G. Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J. Mol. Biol. 281, 523–537 (1998).

    CAS  PubMed  Google Scholar 

  62. Healy, J.I. & Goodnow, C.C. Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. Immunol. 16, 645–670 (1998).

    CAS  PubMed  Google Scholar 

  63. Pierce, S.K. Lipid rafts and B-cell activation. Nature Rev. Immunol. 2, 96–105 (2002).

    CAS  Google Scholar 

  64. Matko, J. & Szollosi, J. Landing of immune receptors and signal proteins on lipid rafts: a safe way to be spatio-temporally coordinated? Immunol. Lett. 82, 3–15 (2002).

    CAS  PubMed  Google Scholar 

  65. Furukawa, K. et al. B lymphoblasts show oxidase activity in response to cross-linking of surface IgM and HLA-DR. Scand. J. Immunol. 35, 561–567 (1992).

    CAS  PubMed  Google Scholar 

  66. Verveer, P.J., Wouters, F.S., Reynolds, A.R. & Bastiaens, P.I. Quantitative imaging of lateral ErbB1 receptor signal propagation in the plasma membrane. Science 290, 1567–1570 (2000).

    CAS  Google Scholar 

  67. Goitsuka, R. et al. BASH, a novel signaling molecule preferentially expressed in B cells of the Bursa of Fabricius. J. Immunol. 161, 5804–5808 (1998).

    CAS  PubMed  Google Scholar 

  68. Wienands, J. et al. SLP-65: A new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. J. Exp. Med. 188, 791–795 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Fu, C., Turck, C.W., Kurosaki, T. & Chan, A.C. BLNK: A central linker protein in B cell activation. Immunity 9, 93–103 (1998).

    CAS  PubMed  Google Scholar 

  70. DeLeo, F.R. et al. Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly. J. Clin. Invest. 101, 455–463 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kawahara, T. et al. Toll-like receptor 4 regulates gastric pit cell responses to Helicobacter pylori infection. J. Med. Invest. 48, 190–197 (2001).

    CAS  PubMed  Google Scholar 

  72. Jumaa, H. et al. Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11, 547–554 (1999).

    CAS  PubMed  Google Scholar 

  73. Bromley, S.K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375–396 (2001).

    CAS  PubMed  Google Scholar 

  74. Batista, F.D., Iber, D. & Neuberger, M.S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).

    CAS  PubMed  Google Scholar 

  75. Rutault, K., Alderman, C., Chain, B.M. & Katz, D.R. Reactive oxygen species activate human peripheral blood dendritic cells. Free Radical Biol. Med. 26, 232–238 (1999).

    CAS  Google Scholar 

  76. Reeves, E.P. et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291–297 (2002).

    CAS  PubMed  Google Scholar 

  77. Bokoch, G.M. Microbial killing: hold the bleach and pass the salt! Nature Immunol. 3, 340–342 (2002).

    CAS  Google Scholar 

  78. Zola, H. The development of antibody responses in the infant. Immunol. Cell. Biol. 75, 587–590 (1997).

    CAS  PubMed  Google Scholar 

  79. van der Veen, R.C. et al. Superoxide prevents nitric oxide-mediated suppression of helper T lymphocytes: decreased autoimmune encephalomyelitis in nicotinamide adenine dinucleotide phosphate oxidase knockout mice. J. Immunol. 164, 5177–5183 (2000).

    CAS  PubMed  Google Scholar 

  80. Peterhans, E. Reactive oxygen species and nitric oxide in viral diseases. Biol. Trace Elem. Res. 56, 107–116 (1997).

    CAS  PubMed  Google Scholar 

  81. Buffinton, G.D., Christen, S., Peterhans, E. & Stocker, R. Oxidative stress in lungs of mice infected with influenza A virus. Free Radical Res. Commun. 16, 99–110 (1992).

    CAS  Google Scholar 

  82. Colamussi, M.L., White, M.R., Crouch, E. & Hartshorn, K.L. Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 93, 2395–2403 (1999).

    CAS  PubMed  Google Scholar 

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  1. Abteilung Molekulare Immunologie, Max-Planck Institute für Immunobiologie, Universität Freiburg, Biologie III, Stuebeweg 51, Freiburg, 79108, Germany

    Michael Reth

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Reth, M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 3, 1129–1134 (2002). https://doi.org/10.1038/ni1202-1129

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