Abstract
This article summarises studies supporting the proposal that induction of L-tryptophan (Trp) degradation along the kynurenine pathway in human monocytes and macrophages by interferon-γ (IFNγ) represents a novel extracellular antioxidant defence that acts to prevent inadvertent oxidative damage to host tissue during inflammation. The studies show that formation and release of the aminophenolic antioxidant 3-hydroxyanthranilic acid (3-HAA) is responsible for the ability of IFNγ-primed human macrophages to inhibit the oxidation of low density lipoprotein (LDL); an event implicated as an important event in atherogenesis. 3-HAA efficiently inhibits LDL oxidation by acting as an aqueous oxidant scavenger and a Synergist for LDL-associated vitamin E. Indoleamine 2,3-dioxygenase activity (IDO) is the initial and rate limiting enzyme of Trp degradation along the kynurenine pathway. Nitric oxide inhibits IDO activity in IFNγ-primed human macrophages and this may represent a physiological regulatory mechanism of the dioxygenase during inflammation.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Alberti-Giani, D., Malherbe, P., Ricciardi-Castanoli, P., Kšhler, C., Denis-Donini, S., and Cesura, A.M., 1997, Differential regulation of indoleamine 2,3-dioxygenase expression by nitric oxide and inflammatory mediators in IFN-γ-activated murine macrophages and microglial cells, J. Immunol. 159:419–426.
Albina, J.E., 1995, On the expression of nitric oxide synthase by human macrophages. Why no NO?, J. Leukoc. Biol. 58:643–649.
Aune, T.M. and Pogue, S.L., 1989, Inhibition of tumor cell growth by interferon-γ is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide, J. Clin. Invest. 84:863–875.
Berliner, J.A. and Heinecke, J.W., 1996, The role of oxidized lipoproteins in atherogenesis, Free Radio. Biol. Med. 20:707–727.
Bisby, R.H. and Parker, A.W., 1991, Reactions of the alpha-tocopheroxyl radical in micellar solutions studied by nanosecond laser flash photolysis, FEBS Lett. 290:205–208.
Bowry, V.W., Mohr, D., Cleary, J., and Stocker, R., 1995, Prevention of tocopherol-mediated peroxidation of ubiquinol-10-free human low density lipoprotein, J. Biol. Chem. 270:5756–5763.
Bowry, V.W. and Stocker, R., 1993, Tocopherol-mediated peroxidation. The pro-oxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein, J. Am. Chem. Soc. 115:6029–6044.
Burton, G.W. and Ingold, K.U., 1986, Vitamin E: Application of the principles of physical organic chemistry to the exploration of its structure and function, Acc. Chem. Res. 19:194–201.
Carlin, J.M., Ozaki, Y., Byrne, G.I., Brown, R.R., and Borden, E.C., 1989, Interferons and indoleamine 2,3-dioxygenase: Role in antimicrobial and antitumor effects, Experientia 45:535–541.
Christen, S., Peterhans, E., and Stocker, R., 1990, Antioxidant activities of some tryptophan metabolites: Possible implication for inflammatory diseases., Proc. Natl. Acad. Sci. U.S.A. 87:2506–2510.
Christen, S., Thomas, S.R., Garner, B., and Stocker, R., 1994, Inhibition by interferon-γ of human mononuclear cell-mediated low density lipoprotein oxidation. Participation of tryptophan metabolism along the kynurenine pathway, J. Clin. Invest. 93:2149–2158.
Daley-Yates, P.T., Powell, A.P., and Smith, L.L., 1988, Pulmonary indoleamine 2,3-dioxygenase activity and its significance in the response of rats, mice, and rabbits to oxidative stress, Toxicol. Appl. Pharmacol. 96:222–232.
Esterbauer, H., Gebicki, J., Puhl, H., and Jürgens, G., 1992, The role of lipid peroxidation and antioxidants in oxidative modification of LDL, Free Radic. Biol. Med. 13:341–390.
Galter, D., Mihm, S., and Dršge, W., 1994, Distinct effects of glutathione disulphide on the nuclear transcription factors κB and the activator protein-1, Eur. J. Biochem. 221:639–648.
Geng, Y., Kodama, T., and Hansson, G.K., 1994, Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation., Arterioscler. Thromb. 14:798–806.
Gupta, S.L., Carlin, J.M., Pyati, P., Dai, W., Pfefferkorn, E.R., and Murphy, M.J., Jr., 1994, Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts, Infect. Immun. 62:2277–2284.
Habara-Ohkubo, A., Shirahata, T., Takikawa, O., and Yoshida, R., 1993, Establishment of an antitoxoplasma state by stable expression of mouse indoleamine 2,3-dioxygenase., Infect. Immun. 61:1810–1813.
Hansson, G.K., Holm, J., and Jonasson, L., 1989, Detection of activated T lymphocytes in the human atherosclerotic plaque, Am. J. Pathol. 135:169–175.
Hayaishi, O., Hirata, F., Ohnishi, T., Henry, J.P., Rosenthal, I., and Katoh, A., 1977, Indoleamine 2,3-dioxygenase. Incorporation of 18O2 and 18O2 into the reaction products, J. Biol. Chem. 252:3548–3550.
Heyes, M.P., Achim, C.L., Wiley, C.A., Major, E.O., Saito, K., and Markey, S.P., 1996, Human microglia convert L-tryptophan into the neurotoxin quinolinic acid, Biochem. J. 320:595–597.
Heyes, M.P., Saito, K., Crowley, J.S., Davis, L.E., Demitrack, M.A., Der, M., Dilling, L.A., Elia, J., Kruesi, M.J.P, Lackner, A., Larsen, S.A., Lee, K., Leonard, H.L., MArkey, S.P., Martin, A., Milstein, S., Mouradian, M.M., Pranzatelli, M.R., Quearry, B.J., Salazar, A., Smith, M., Strauss, S.E., Sunderland, T., Swedo, S.W., and Tourtellotte, W.W., 1992, Quinolinic acid and kynurenic pathway metabolism in inflammatory and non-inflammatory neurological disease, Brain 115:1249–1273.
Heyes, M.P., Saito, K., and Markey, S.P., 1992, Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid., Biochem. J. 283:633–635.
Jessup, W., Mohr, D., Gieseg, S.P., Dean, R.T., and Stocker, R., 1992, The participation of nitric oxide in cell free-and its restriction of macrophage-mediated oxidation of low-density lipoprotein, Biochim. Biophys. Acta 1180:73–82.
Meyer, M., Schreck, R., and Baeuerle, P.A., 1993, H2O2 and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor, EMBO J. 12:2005–2015.
Mukai, K., Morimoto, H., Okauchi, Y., and Nagaoka, S., 1993, Kinetic study of reactions between toco-pheroxyl radicals and fatty acids, Lipids 28:753–756.
Nathan, C.F., 1992, Nitric oxide as a secretory product of mammalian cells, FASEB J. 6:3051–3064.
Nathan, C.F., and Yoshida, R. 1988, Cytokines: Interferon-γ. Inflammation: Basic Principles and Clinical Correlates., Volume 1 (J.I. Gallin, I.M. Goldstein, and R. Snyderman, eds.). New York, Raven Press. 229–251.
Neuzil, J., Thomas, S.R., and Stocker, R., 1997, Requirement for, promotion, or inhibition by α-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation, Free Radic. Biol. Med. 22:57–71.
O’Donnell, V.B., Chumley, H., Hogg, N, Bloodsworth, A., Darley-Usmar, V.M., and Freeman, B.A., 1997, Nitric oxide inhibition of lipid peroxidation: kinetics of reaction with lipid peroxyl radicals and comparison with α-tocopherol, Biochemistry. 36:15216–15223.
Ohnishi, T., Hirata, F., and Hayaishi, O., 1977, Indoleamine 2,3-dioxygenase. Potassium Superoxide as substrate., J. Biol. Chem. 252(13):4643–4647.
Pfefferkorn, E.R., 1984, Interferon γ blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cell to degrade tryptophan, Proc. Natl. Acad. Sci. U.S.A. 81:908–912.
Radi, R., 1996, Reactions of nitric oxide with metalloproteins, Chem. Res. Toxicol. 9:828–835.
Sanni, L.A., Thomas, S.R., Tattam, B.N., Moore, D.E., Chaudhri, G,, Stocker, R., and Hunt, N.H., 1998, Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria, Am. J. Pathol. 152:611–619.
Schenk, H., Klein, M., Erdbrugger, W., Dršge, W., and Schulze Osthoff, K., 1994, Distinct effects of thiore-doxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1., Proc. Natl. Acad. Sci. U.S.A. 91:1672–1676.
Schmidt, H.H. and Walter, U., 1994, NO at work, Cell 78:919–925.
Staal, F.J.T., Roederer, M., Herzenberg, L.A., and Herzenberg, L.A., 1990, Intracellular thiols regulate activation of nuclear factor κB and transcription of human immunodeficiency virus, Proc. Natl. Acad. Sci. U.S.A. 87:9943–9947.
Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L., 1989, Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity, N. Engl. J. Med. 320:915–924.
Sun, Y., 1989, Indoleamine 2,3-dioxygenase-a new antioxidant enzyme, Mater. Med. Pol. 21:244–250.
Takikawa, O., Kuroiwa, T., Yamazaki, F., and Kido, R., 1988, Mechanism of interferon-γ action. Characterization of indoleamine 2,3 dioxygenase in cultured human cells induced by interferon-γ and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity, J. Biol. Chem. 263:2041–2048.
Taylor, M.W. and Feng, G.S., 1991, Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism, FASEB J. 5:2516–2522.
Thomas, S.M., Garrity, L.F., Brandt, C.R., Schobert, C.S., Feng, G.S., Taylor, M.W., Carlin, J.M., and Byrne, G.I., 1993, IFN-gamma-mediated antimicrobial response. Indoleamine 2,3-dioxygenase-deficient mutant host cells no longer inhibit intracellular Chlamydia or Toxoplasma growth., J. Immunol. 150:5529–5534.
Thomas, S.R., Davies, M.J., and Stocker, R., 1998, Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite, Chem. Res. Toxicol. 11:484–494.
Thomas, S.R., Mohr, D., and Stocker, R., 1994, Nitric oxide inhibits indoleamine 2,3-dioxygenase activity in interferonγ-primed mononuclear phagocytes, J. Biol. Chem. 269:14457–14464.
Thomas, S.R., Neuzil, J., and Stocker, R., 1996a, Co-supplementation with coenzyme Q prevents the prooxidant effect of α-tocopherol and increases the resistance of low-density lipoprotein towards transition metal-dependent oxidation initiation, Arterioscl. Thromb. Vasc. Biol. 16:687–696.
Thomas, S.R., Witting, P.K., and Stocker, R., 1996b, 3-Hydroxyanthranilic acid is an efficient, cell-derived co-antioxidant for α-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation, J. Biol. Chem. 271:32714–32721.
Uyemura, K., Demer, L.L., Castle, S.C., Jullien, D., Berliner, J.A., Gately, M.K., Warrier, R.R., Pham, N., Fogelman, A.M., and Modlin, R.L., 1996, Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis, J. Clin. Invest. 97:2130–2138.
Waldeck, A.R. and Stocker, R., 1996, Radical-initiated lipid peroxidation in low density lipoproteins: Insights obtained from kinetic modeling, Chem. Res. Toxicol. 9:954–964.
Werner-Felmayer, G., Werner, E.R., Fuchs, D., Hausen, A., Reibnegger, G., and Wachter, H., 1989, Characteristics of interferon induced tryptophan metabolism in human cells in vitro, Biochim. Biophys. Acta 1012:140–147.
Xu, Q., Oberhuber, G., Gruschwitz, M., and Wick, G., 1990, Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens, Clin. Immunol. Immunopathol. 56:344–359.
Yoshida, R., Urade, Y., Tokuda, M., and Hayaishi, O., 1979, Induction of indoleamine 2,3-dioxygenase in mouse lung during virus Infection, Proc. Natl. Acad. Sci. U.S.A. 76:4084–4086.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Thomas, S.R., Stocker, R. (1999). Antioxidant Activities and Redox Regulation of Interferon-Gamma-Induced Tryptophan Metabolism in Human Monocytes and Macrophages. In: Huether, G., Kochen, W., Simat, T.J., Steinhart, H. (eds) Tryptophan, Serotonin, and Melatonin. Advances in Experimental Medicine and Biology, vol 467. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4709-9_67
Download citation
DOI: https://doi.org/10.1007/978-1-4615-4709-9_67
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7133-5
Online ISBN: 978-1-4615-4709-9
eBook Packages: Springer Book Archive