Skip to main content
Download PDF

Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase

Cellular & Molecular Biology Letters volume 12, pages 82–102 (2007)Cite this article

Abstract

The activity of indoleamine 2, 3-dioxygenase (IDO; E.C. 1.13.11.42) catalyzes the oxidative cleavage of tryptophan to form kynurenine. IDO activity consumes superoxide anions; therefore, we postulated that over-expression of IDO might mitigate superoxide-anion dependent, oxidative modification of cellular proteins in vitro. We prepared and characterized RAW 264.7 macrophages that were stably transfected with either an IDO expression vector or the control (empty) vector. We detected IDO mRNA, protein, and enzyme activity in the IDO-transfected macrophages, but not in the macrophages transfected with the empty vector. To generate superoxide anions in situ, we treated the IDO-and control-transfected cultures with xanthine or hypoxanthine, and then used ELISA methods to quantitate the relative levels of oxidatively modified proteins in total cell lysates. The levels of protein carbonyls were similar in IDO-transfected and vector-transfected macrophages; however, protein nitration was significantly less in IDO-transfected cells compared to control transfectants. In addition, steady-state levels of superoxide anions were significantly lower in the IDO-transfected cultures compared with control transfectants. Our results are consistent with the concept that, besides degrading tryptophan, IDO activity may protect cells from oxidative damage.

Abbreviations

CMV:

cytomegalovirus

H2O2 :

hydrogen peroxide

IDO:

indoleamine 2,3-dioxygenase

NAD:

nicotinamide adenine dinucleotid

NO:

nitric oxide

ONOO-:

peroxynitrite

O2 ⊎- :

superoxide anion

PBS:

phosphate buffered saline (pH 7.4)

ROS:

reactive oxygen species

SOD:

superoxide dismutase

References

  1. Hayaishi, O. Properties and function of indoleamine 2,3-dioxygenase. J. Biochem. 79 (1976) 13P–21P.

    PubMed  CAS  Google Scholar 

  2. Shimizu, T., Nomiyama, S., Hirata, F. and Hayaishi, O. Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem. 253 (1978) 4700–4706.

    PubMed  CAS  Google Scholar 

  3. Yoshida, R., Nukiwa, T., Watanabe, Y., Fujiwara, M., Hirata, F. and Hayaishi, O. Regulation of indoleamine 2,3-dioxygenase activity in the small intestine and the epididymis of mice. Arch. Biochem. Biophys. 203 (1980) 343–351.

    PubMed  Article  CAS  Google Scholar 

  4. Watanabe, Y., Yoshida, R., Sono, M. and Hayaishi, O. Immunohistochemical localization of indoleamine 2,3-dioxygenase in the argyrophilic cells of rabbit duodenum and thyroid gland. J. Histochem. Cytochem. 29 (1981) 623–632.

    PubMed  CAS  Google Scholar 

  5. Yoshida, R., Imanishi, J., Oku, T., Kishida, T. and Hayaishi, O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc. Natl. Acad. Sci. U.S.A. 78 (1981) 129–132.

    PubMed  Article  CAS  Google Scholar 

  6. Pfefferkorn, E.R., Rebhun, S. and Eckel, M. Characterization of an indoleamine 2,3-dioxygenase induced by gamma-interferon in cultured human fibroblasts. J. Interferon Res. 6 (1986) 267–279.

    PubMed  CAS  Google Scholar 

  7. Yoshida, R. and Hayaishi, O. Indoleamine 2,3-dioxygenase. Methods Enzymol. 142 (1987) 188–195.

    PubMed  CAS  Google Scholar 

  8. Carlin, J.M., Borden, E.C., Sondel, P.M. and Byrne, G.I. Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes. J. Leukoc. Biol. 45 (1989) 29–34.

    PubMed  CAS  Google Scholar 

  9. Saito, K., Markey, S.P. and Heyes, M.P. Chronic effects of gamma-interferon on quinolinic acid and indoleamine-2,3-dioxygenase in brain of C57BL6 mice. Brain Res. 546 (1991) 151–154.

    PubMed  Article  CAS  Google Scholar 

  10. Gupta, S.L., Carlin, J.M., Pyati, P., Dai, W., Pfefferkorn, E.R. and Murphy, M.J., Jr. Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts. Infect Immun. 62 (1994) 2277–2284.

    PubMed  CAS  Google Scholar 

  11. Malina, H.Z. and Martin, X.D. Indoleamine 2,3-dioxygenase: antioxidant enzyme in the human eye. Graefes Arch. Klin. Exp. Ophthalmol. 234 (1996) 457–462.

    Article  CAS  Google Scholar 

  12. Hansen, A.M., Driussi, C., Turner, V., Takikawa, O. and Hunt, N.H. Tissue distribution of indoleamine 2,3-dioxygenase in normal and malaria-infected tissue. Redox Rep. 5 (2000) 112–115.

    PubMed  Article  CAS  Google Scholar 

  13. Kudo, Y. and Boyd, C.A. Human placental indoleamine 2,3-dioxygenase: cellular localization and characterization of an enzyme preventing fetal rejection. Biochim. Biophys. Acta 1500 (2000) 119–124.

    PubMed  CAS  Google Scholar 

  14. Daubener, W., Spors, B., Hucke, C., Adam, R., Stins, M., Kwang Sik, K. and Schroten, H. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect. Immun. 69 (2001) 6527–6531.

    PubMed  Article  CAS  Google Scholar 

  15. Sedlmayr, P., Blaschitz, A., Wintersteiger, R., Semlitsch, M., Hammer, A., MacKenzie, C.R., Walcher, W., Reich, O., Takikawa, O. and Dohr, G. Localization of indoleamine 2,3-dioxygenase in human female reproductive organs and the placenta. Mol. Hum. Reprod. 8 (2002) 385–391.

    PubMed  Article  CAS  Google Scholar 

  16. de la Maza, L.M. and Peterson, E.M. Dependence of the in vitro antiproliferative activity of recombinant human gamma-interferon on the concentration of tryptophan in culture media. Cancer Res. 48 (1988) 346–350.

    PubMed  Google Scholar 

  17. Schroten, H., Spors, B., Hucke, C., Stins, M., Kim, K.S., Adam, R. and Daubener, W. Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: inhibition of Staphylococcus aureus by activation of indoleamine 2,3-dioxygenase. Neuropediatrics 32 (2001) 206–210.

    PubMed  Article  CAS  Google Scholar 

  18. Hayashi, T., Rao, S.P., Takabayashi, K., Van Uden, J.H., Kornbluth, R.S., Baird, S.M., Taylor, M.W., Carson, D.A. Catanzaro, A. and Raz, E. Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase. Infect. Immun. 69 (2001) 6156–6164.

    PubMed  Article  CAS  Google Scholar 

  19. Rottenberg, M.E., Gigliotti Rothfuchs, A., Gigliotti, D., Ceausu, M., Une, C., Levitsky, V. and Wigzell, H. Regulation and role of IFN-gamma in the innate resistance to infection with Chlamydia pneumoniae. J. Immunol. 164 (2000) 4812–4818.

    PubMed  CAS  Google Scholar 

  20. Ceravolo, I.P., Chaves, A.C., Bonjardim, C.A., Sibley, D., Romanha, A.J. and Gazzinelli, R.T. Replication of Toxoplasma gondii, but not Trypanosoma cruzi, is regulated in human fibroblasts activated with gamma interferon: requirement of a functional JAK/STAT pathway. Infect. Immun. 67 (1999) 2233–2240.

    PubMed  CAS  Google Scholar 

  21. Jacoby, D.B. and Choi, A.M. Influenza virus induces expression of antioxidant genes in human epithelial cells. Free Radic. Biol. Med. 16 (1994) 821–824.

    PubMed  Article  CAS  Google Scholar 

  22. Heyes, M.P., Saito, K., Crowley, J.S., Davis, L.E., Demitrack, M.A., Der, M., Dilling, L.A., Elia, J., Kruesi, M.J., Lackner, A. and et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and noninflammatory neurological disease. Brain 115 (1992) 1249–1273.

    PubMed  Google Scholar 

  23. Mellor, A.L., Keskin, D.B., Johnson, T., Chandler, P. and Munn, D.H. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J. Immunol. 168 (2002) 3771–3776.

    PubMed  CAS  Google Scholar 

  24. Munn, D.H., Shafizadeh, E., Attwood, J.T., Bondarev, I., Pashine, A. and Mellor, A.L. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189 (1999) 1363–1372.

    PubMed  Article  CAS  Google Scholar 

  25. Sun, Y. Indoleamine 2,3-dioxygenase—a new antioxidant enzyme. Mater Med. Pol. 21 (1989) 244–250.

    PubMed  CAS  Google Scholar 

  26. Christen, S., Peterhans, E. and Stocker, R. Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 2506–2510.

    PubMed  Article  CAS  Google Scholar 

  27. Thomas, S.R. and Stocker, R. Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Rep. 4 (1999) 199–220.

    PubMed  Article  CAS  Google Scholar 

  28. Hirata, F. and Hayaishi, O. Studies on indoleamine 2,3-dioxygenase. I. Superoxide anion as substrate. J. Biol. Chem. 250 (1975) 5960–5966.

    PubMed  CAS  Google Scholar 

  29. Sono, M. The roles of superoxide anion and methylene blue in the reductive activation of indoleamine 2,3-dioxygenase by ascorbic acid or by xanthine oxidase-hypoxanthine. J. Biol. Chem. 264 (1989) 1616–1622.

    PubMed  CAS  Google Scholar 

  30. Kobayashi, K., Hayashi, K. and Sono, M. Effects of tryptophan and pH on the kinetics of superoxide radical binding to indoleamine 2,3-dioxygenase studied by pulse radiolysis. J. Biol. Chem. 264 (1989) 15280–15283.

    PubMed  CAS  Google Scholar 

  31. Ozaki, Y., Nichol, C.A. and Duch, D.S. Utilization of dihydroflavin mononucleotide and superoxide anion for the decyclization of L-tryptophan by murine epididymal indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys. 257 (1987) 207–216.

    PubMed  Article  CAS  Google Scholar 

  32. Taniguchi, T., Hirata, F. and Hayaishi, O. Intracellular utilization of superoxide anion by indoleamine 2,3-dioxygenase of rabbit enterocytes. J. Biol. Chem. 252 (1977) 2774–2776.

    PubMed  CAS  Google Scholar 

  33. Halliwell, B. The biological effects of the superoxide radical and its products. Bull. Eur. Physiopathol. Respir. 17 (1981) 21–29.

    PubMed  CAS  Google Scholar 

  34. Halliwell, B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Amer. J. Med. 91 (1991) 14S–22S.

    PubMed  Article  CAS  Google Scholar 

  35. Halliwell, B. Mechanisms involved in the generation of free radicals. Pathol. Biol. (Paris) 44 (1996) 6–13.

    CAS  Google Scholar 

  36. Halliwell, B. and Chirico, S. Lipid peroxidation: its mechanism, measurement, and significance. Am. J. Clin. Nutr. 57 (1993) 715S–724S; discussion 724S-725S.

    PubMed  CAS  Google Scholar 

  37. Halliwell, B. and Aruoma, O.I. DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett. 281 (1991) 9–19.

    PubMed  Article  CAS  Google Scholar 

  38. Levine, R.L. and Stadtman, E.R. Oxidative modification of proteins during aging. Exp. Gerontol. 36 (2001) 1495–1502.

    PubMed  Article  CAS  Google Scholar 

  39. Stadtman, E.R. and Levine, R.L. Protein oxidation. Ann. N. Y. Acad. Sci. 899 (2000) 191–208.

    PubMed  CAS  Article  Google Scholar 

  40. Tien, M., Berlett, B.S., Levine, R.L., Chock, P.B. and Stadtman, E.R. Peroxynitrite-mediated modification of proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation, tyrosine nitration, and methionine oxidation. Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 7809–7814.

    PubMed  Article  CAS  Google Scholar 

  41. Stadtman, E.R. and Berlett, B.S. Reactive oxygen-mediated protein oxidation in aging and disease. Drug Metab. Rev. 30 (1998) 225–243.

    PubMed  CAS  Google Scholar 

  42. Griffiths, H.R. Antioxidants and protein oxidation. Free Radic. Res. 33 (2000) S47–S58.

    PubMed  CAS  Google Scholar 

  43. Levine, R.L., Wehr, N., Williams, J.A., Stadtman, E.R. and Shacter, E. Determination of carbonyl groups in oxidized proteins. Meth. Mol. Biol. 99 (2000) 15–24.

    CAS  Google Scholar 

  44. Levine, R.L. Carbonyl modified proteins in cellular regulation, aging, and disease. Free Radic. Biol. Med. 32 (2002) 790–796.

    PubMed  Article  CAS  Google Scholar 

  45. Betteridge, D.J. What is oxidative stress? Metabolism 49 (2000) 3–8.

    PubMed  CAS  Google Scholar 

  46. Lehucher-Michel, M.P., Lesgards, J.F., Delubac, O., Stocker, P., Durand, P. and Prost, M. Oxidative stress and human disease: Current knowledge and perspectives for prevention. Presse Med. 30 (2001) 1076–1081.

    PubMed  CAS  Google Scholar 

  47. Witztum, J.L. and Steinberg, D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc. Med. 11 (2001) 93–102.

    PubMed  Article  CAS  Google Scholar 

  48. Traverso, N. Oxidative elements in the pathogenesis of atherosclerosis. Ital. Heart J. 2 (2001) 37S–39S.

    PubMed  Google Scholar 

  49. Kovacic, P. and Jacintho, J.D. Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr. Med. Chem. 8 (2001) 773–796.

    PubMed  CAS  Google Scholar 

  50. Kawanishi, S., Hiraku, Y. and Oikawa, S. Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging, Mutat. Res. 488 (2001) 65–76.

    PubMed  Article  CAS  Google Scholar 

  51. Lipinski, B. Pathophysiology of oxidative stress in diabetes mellitus. J. Diabetes Complicat. 15 (2001) 203–210.

    PubMed  Article  CAS  Google Scholar 

  52. Odeh, M. New insights into the pathogenesis and treatment of rheumatoid arthritis. Clin. Immunol. Immunopathol. 83 (1997) 103–116.

    PubMed  Article  CAS  Google Scholar 

  53. Stangel, M., Mix, E., Zettl, U.K. and Gold, R. Oxides and apoptosis in inflammatory myopathies. Microsc. Res. Tech. 55 (2001) 249–258.

    PubMed  Article  CAS  Google Scholar 

  54. Smith, K.J., Kapoor, R. and Felts, P.A. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 9 (1999) 69–92.

    PubMed  CAS  Article  Google Scholar 

  55. Mantle, D. and Preedy, V.R. Free radicals as mediators of alcohol toxicity. Adverse Drug React. Toxicol. Rev. 18 (1999) 235–252.

    PubMed  CAS  Google Scholar 

  56. Bailey, S.M. and Cunningham, C.C. Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Radic. Biol. Med. 32 (2002) 11–16.

    PubMed  Article  CAS  Google Scholar 

  57. Milhavet, O. and Lehmann, S. Oxidative stress and the prion protein in transmissible spongiform encephalopathies. Brain Res. Rev. 38 (2002) 328–339.

    PubMed  Article  CAS  Google Scholar 

  58. Contestabile, A. Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives. Curr. Top Med. Chem. 1 (2001) 553–568.

    PubMed  Article  CAS  Google Scholar 

  59. Sayre, L.M., Smith, M.A. and Perry, G. Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr. Med. Chem. 8 (2001) 721–738.

    PubMed  CAS  Google Scholar 

  60. Marshall, B., Keskin, D.B. and Mellor, A.L. Regulation of prostaglandin synthesis and cell adhesion by a tryptophan catabolizing enzyme. BMC Biochem. 2 (2001) 5.

    PubMed  Article  CAS  Google Scholar 

  61. Hayaishi, O. Utilization of superoxide anion by indoleamine oxygenasecatalyzed tryptophan and indoleamine oxidation. Adv. Exp. Med. Biol. 398 (1996) 285–289.

    PubMed  CAS  Google Scholar 

  62. Quick, K.L., Hardt, J.I. and Dugan, L.L. Rapid microplate assay for superoxide scavenging efficiency. J. Neurosci. Methods 97 (2000) 139–144.

    PubMed  Article  CAS  Google Scholar 

  63. Lowenstein, C.J., Alley, E.W., Raval, P., Snowman, A.M., Snyder, S.H., Russell, S.W. and Murphy, W.J. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. U. S. A. 90 (1993) 9730–9734.

    PubMed  Article  CAS  Google Scholar 

  64. Ducrocq, C., Blanchard, B., Pignatelli, B. and Ohshima, H. Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell Mol. Life Sci. 55 (1999) 1068–1077.

    PubMed  Article  CAS  Google Scholar 

  65. Hornbeck, P., Winston, S. and Fuller, S.A. in: Current Protocols in Molecular Biology (Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A. and Struhl, K., Eds.), John Wiley & Sons, New York.1991, Vol. 2, pp. 11.2.

    Google Scholar 

  66. Levine, R.L., Williams, J.A., Stadtman, E.R. and Shacter, E. Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol. 233 (1994) 346–363.

    PubMed  CAS  Article  Google Scholar 

  67. Buss, H., Chan, T.P., Sluis, K.B., Domigan, N.M. and Winterbourn, C.C. Protein carbonyl measurement by a sensitive ELISA method. Free Radic. Biol. Med. 23 (1997) 361–366.

    PubMed  Article  CAS  Google Scholar 

  68. Wood, J.M., Ehrke, C. and Schallreuter, K.U. Tryptophan protects human melanoma cells against gamma-interferon and tumour necrosis factor-alpha: a unifying mechanism of action. Melanoma Res. 1 (1991) 177–185.

    PubMed  CAS  Google Scholar 

  69. Daley-Yates, P.T., Powell, A.P. and Smith, L.L. Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress. Toxicol. Appl. Pharmacol. 96 (1988) 222–232.

    PubMed  Article  CAS  Google Scholar 

  70. Goda, K., Hamane, Y., Kishimoto, R. and Ogishi, Y. Radical scavenging properties of tryptophan metabolites. Estimation of their radical reactivity. Adv. Exp. Med. Biol. 467 (1999) 397–402.

    PubMed  CAS  Google Scholar 

  71. Thomas, S.R. and Stocker, R. Antioxidant activities and redox regulation of interferon-gamma-induced tryptophan metabolism in human monocytes and macrophages. Adv. Exp. Med. Biol. 467 (1999) 541–552.

    PubMed  CAS  Google Scholar 

  72. Grant, R.S., Naif, H., Espinosa, M. and Kapoor, V. IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress. Redox Rep. 5 (2000) 101–104.

    PubMed  Article  CAS  Google Scholar 

  73. Grant, R.S., Passey, R., Matanovic, G., Smythe, G. and Kapoor, V., Evidence for increased de novo synthesis of NAD in immune-activated RAW264.7 macrophages: a self-protective mechanism? Arch. Biochem. Biophys. 372 (1999) 1–7.

    PubMed  Article  CAS  Google Scholar 

  74. Alberati-Giani, D., Ricciardi-Castagnoli, P., Köhler, C. and Cesura, A.M. Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J. Neurochem. 66 (1996) 996–1004.

    PubMed  CAS  Article  Google Scholar 

  75. Knight, J.A. Review: Free radicals, antioxidants, and the immune system. Ann. Clin. Lab. Sci. 30 (2000) 145–158.

    PubMed  CAS  Google Scholar 

  76. Klebanoff, S.J., Locksley, R.M., Jong, E.C. and Rosen, H. Oxidative response of phagocytes to parasite invasion. Ciba Found. Symp. 99 (1983) 92–112.

    PubMed  CAS  Google Scholar 

  77. Fridovich, I. Biological effects of the superoxide radical. Arch. Biochem. Biophys. 247 (1986) 1–11.

    PubMed  Article  CAS  Google Scholar 

  78. Schisler, N.J. and Singh, S.M. Tissue-specific developmental regulation of superoxide dismutase (SOD-1 and SOD-2) activities in genetic strains of mice. Biochem. Genet. 23 (1985) 291–308.

    PubMed  Article  CAS  Google Scholar 

  79. Zelko, I.N., Mariani, T.J. and Folz, R.J. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and ECSOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med. 33 (2002) 337–349.

    PubMed  Article  CAS  Google Scholar 

  80. Grankvist, K., Marklund, S.L. and Taljedal, I.B. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem. J. 199 (1981) 393–398.

    PubMed  CAS  Google Scholar 

  81. Halliwell, B. Biochemical mechanisms accounting for the toxic action of oxygen on living organisms: the key role of superoxide dismutase. Cell Biol. Int. Rep. 2 (1978) 113–128.

    PubMed  Article  CAS  Google Scholar 

  82. Hayaishi, O. and Yoshida, R. Specific induction of pulmonary indoleamine 2,3-dioxygenase by bacterial lipopolysaccharide. Ciba Found. Symp. (1978) 199–203.

  83. Kamimura, S., Eguchi, K., Yonezawa, M. and Sekiba, K. Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta. Acta Med. Okayama 45 (1991) 135–139.

    PubMed  CAS  Google Scholar 

  84. Cook, J.S., Pogson, C.I. and Smith, S.A. Indoleamine 2,3-dioxygenase. A new, rapid, sensitive radiometric assay and its application to the study of the enzyme in rat tissues. Biochem. J. 189 (1980) 461–466.

    PubMed  CAS  Google Scholar 

  85. Takikawa, O., Yoshida, R., Kido, R. and Hayaishi, O. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J. Biol. Chem. 261 (1986) 3648–3653.

    PubMed  CAS  Google Scholar 

  86. Fujiwara, M., Shibata, M., Watanabe, Y., Nukiwa, T., Hirata, F., Mizuno, N. and Hayaishi, O. Indoleamine 2,3-dioxygenase. Formation of L-kynurenine from L-tryptophan in cultured rabbit pineal gland. J. Biol. Chem. 253 (1978) 6081–6085.

    PubMed  CAS  Google Scholar 

  87. Gál, E.M. and Sherman, A.D. L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem. Res. 5 (1980) 223–239.

    PubMed  Article  Google Scholar 

  88. Takikawa, O., Littlejohn, T.K. and Truscott, R.J. Indoleamine 2,3-dioxygenase in the human lens, the first enzyme in the synthesis of UV filters. Exp. Eye Res. 72 (2001) 271–277.

    PubMed  Article  CAS  Google Scholar 

  89. Taylor, M.W. and Feng, G. Relationship between interferon-g, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 5 (1991) 2516–2522.

    PubMed  CAS  Google Scholar 

  90. Heyes, M.P., Achim, C.L., Wiley, C.A., Major, E.O., Saito, K. and Markey, S.P. Human microglia convert L-tryptophan into the neurotoxin quinolinic acid. Biochem. J. 320 (1996) 595–597.

    PubMed  CAS  Google Scholar 

  91. Heyes, M.P., Chen, C.Y., Major, E.O. and Saito, K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem. J. 326 (1997) 351–356.

    PubMed  CAS  Google Scholar 

  92. Santoso, D.I., Rogers, P., Wallace, E.M., Manuelpillai, U., Walker, D. and Subakir, S.B. Localization of indoleamine 2,3-dioxygenase and 4-hydroxynonenal in normal and pre-eclamptic placentae. Placenta 23 (2002) 373–379.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Derin B. Keskin

    Present address: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

  2. Debra A. Gearhart

    Present address: Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, 30912, USA

Authors and Affiliations

  1. Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, 30912, USA

    Derin B. Keskin, Brendan Marshall, David Munn & Andrew L. Mellor

  2. Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, 30912, USA

    Debra A. Gearhart

  3. Department of Veterans Affairs Medical Center Medical Research Service, Augusta, Georgia, USA

    Debra A. Gearhart

Authors
  1. Derin B. Keskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendan Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Munn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew L. Mellor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Debra A. Gearhart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Derin B. Keskin or Debra A. Gearhart.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Keskin, D.B., Marshall, B., Munn, D. et al. Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase. Cell Mol Biol Lett 12, 82–102 (2007). https://doi.org/10.2478/s11658-006-0048-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-006-0048-9

Key words

  • RAW 264.7 macrophages
  • Indoleamine 2, 3-dioxygenase
  • Oxidative stress
  • Protein oxidation
  • Superoxide anion

Cellular & Molecular Biology Letters

ISSN: 1689-1392

Contact us