Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-29T01:12:36.706Z Has data issue: false hasContentIssue false
  • English
  • Français

Glutathione and immune function

Published online by Cambridge University Press:  28 February 2007

Wulf Dröge  and
Raoul Breitkreutz
Wulf Dröge*
Affiliation:
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
Raoul Breitkreutz
Affiliation:
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
*
Corresponding Author: Professor Wulf Dröge, fax +49 6221 423746, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. This factor has been studied most extensively in the case of human immunodeficiency virus (HIV)-infected patients who were found to experience, on average, a massive loss of S equivalent to a net loss of approximately 4 g cysteine/d. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions.

Keywords

GlutathioneImmunityCysteine
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 59 , Issue 4 , November 2000 , pp. 595 - 600
Copyright
Copyright © The Nutrition Society 2000

References

Adler, V, Yin, Z, Tew, KD & Ronai, Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18, 6104–6111.CrossRefGoogle ScholarPubMed
Akerlund, B, Jarstrand, C, Lindeke, B, Sönnerborg, A, Akerblad, A-Ac, & Rasool, O (1996) Effect of N-acetylcysteine (NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. European Journal of Clinical Pharmacology 50, 457–461.Google ScholarPubMed
Allison, JB, Anderson, JA & Seeley, RD (1947) Some effects of methionine on the utilization of nitrogen in the adult dog. Journal of Nutrition 33, 361–370.CrossRefGoogle ScholarPubMed
Beutler, E (1989) Nutritional and metabolic aspects of glutathione. Annual Review of Nutrition 9, 287–302.CrossRefGoogle ScholarPubMed
Breithaupt, T, Eylar, EH, Baez, I, Vasquez, A, Colon-Martinez, S, Rodriquez, J & Kesseler, M (1996) N-acetylcysteine (NAC) reverses the supposed mitogenic responses of CD4+ and CD8+ T cells from aged rhesus monkeys. FASEB Journal 10, 1849 Abstr.Google Scholar
Breitkreutz, R, Holm, S, Pittack, N, Beichert, M, Babylon, A, Yodoi, J & Dröge, W (2000 a) Massive loss of sulphur in HIV infection. AIDS Research and Human Retroviruses 3, 203–209.CrossRefGoogle Scholar
Breitkreutz, R, Pittak, N, Nebe, CT, Schuster, D, Brust, J, Beichert, M, Hack, V, Daniel, V, Edler, L & Dröge, W (2000 b) Improvement of immune functions in HIV infection by sulfur supplementation – two randomized trials. Journal of Molecular Medicine 78, 55–62.CrossRefGoogle ScholarPubMed
Buhl, R, Holroyd, K, Mastrangeli, A, Cantin, AM, Jaffe, HA, Wells, FB, Saltini, C & Crystal, RG (1989) Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet ii, 1294–1298.CrossRefGoogle Scholar
De Quay, B, Malinverni, R & Lauterburg, BH (1992) Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine. AIDS 6, 815–819.CrossRefGoogle ScholarPubMed
Dröge, W (1989) Metabolische Störungen bei HIV-Infektion (Metabolic disturbances with HIV infection). In Project News , no. 2, p. 4. Berlin, Germany: AIDS-Zentrum des Bundesgesundheitsamtes.Google Scholar
Dröge, W & Breitkreutz, R (1999) N-acetyl-cysteine in the therapy of HIV-positive patients. Current Opinion in Clinical Nutrition and Metabolic Care 2, 493–498.CrossRefGoogle ScholarPubMed
Dröge, W, Eck, H-P, & Mihm, S (1992) HIV-induced cysteine deficiency and T cell dysfunctions – a rationale for treatment with N-acetyl-cysteine. Immunology Today 13, 211–214.CrossRefGoogle Scholar
Dröge, W, Eck, H-P, Näher, H, Pekar, U & Daniel, V (1988) Abnormal amino acid concentrations in the blood of patients with acquired immune deficiency syndrome (AIDS) may contribute to the immunological defect. Biological Chemistry Hoppe-Seyler 369, 143–148.CrossRefGoogle Scholar
Dröge, W & Holm, E (1997) Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB Journal 11, 1077–1089.CrossRefGoogle ScholarPubMed
Dröge, W, Schulze-Osthoff, K, Mihm, S, Galter, D, Schenk, H, Eck, H-P, Roth, S & Gmünder, H (1994) Function of glutathione and glutathione disulfide in immunology and immunopathology. FASEB Journal 8, 1131–1138.CrossRefGoogle ScholarPubMed
Eck, H-P, Gmünder, H, Hartmann, M, Petzoldt, D, Daniel, V & Dröge, W (1989) Low concentrations of acid soluble thiol (cysteine) in the blood plasma of HIV-1 infected patients. Biological Chemistry Hoppe-Seyler 370, 101–108.CrossRefGoogle ScholarPubMed
Eck, H-P, Stahl-Hennig, H, Hunsmann, G & Dröge, W (1991) Metabolic disorder as an early consequence of simian immunodeficiency virus infection in rhesus monkeys. Lancet 338, 346–347.CrossRefGoogle Scholar
Fanger, MW, Hart, DA, Wells, JV & Nisonoff, A (1970) Enhancement by reducing agents of the transformation of human and rabbit peripheral lymphocytes. Journal of Immunology 105, 1043–1045.CrossRefGoogle ScholarPubMed
Galter, D, Mihm, S & Droge, W (1994) Distinct effects of glutathione disulphide on the nuclear transcription factor kappa B and the activator protein-1. European Journal of Biochemistry 221, 639–648.CrossRefGoogle ScholarPubMed
Gmünder, H & Dröge, W (1991) Differential effects of glutathione depletion on T cell subsets. Cellular Immunology 138, 229–237.CrossRefGoogle ScholarPubMed
Gmünder, H, Eck, H-P, Benninghoff, B, Roth, S & Dröge, W (1990 a) Macrophages regulate intracellular glutathione levels of lymphocytes. Cellular Immunology 129, 32–46.CrossRefGoogle ScholarPubMed
Gmünder, H, Roth, S, Eck, H-P, Gallas, H, Mihm, S & Dröge, W (1990 b) Interleukin-2 mRNA expression, lymphokine production and DNA synthesis in glutathione-depleted T cells. Cellular Immunology 130, 520–528.CrossRefGoogle ScholarPubMed
Gross, A, Hack, V, Stahl-Hennig, C & Dröge, W (1996) Elevated hepatic γ-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques. AIDS Research and Human Retroviruses 12, 1639–1641.Google ScholarPubMed
Hack, V, Schmid, D, Breitkreutz, R, Stahl-Hennig, C, Drings, P, Kinscherf, R, Taut, F, Holm, E & Dröge, W (1997) Cystine levels, cystine flux and protein catabolism in cancer cachexia, HIV/SIV infection and senescence. FASEB Journal 11, 84–92.CrossRefGoogle ScholarPubMed
Hamilos, DL & Wedner, HJ (1985) The role of glutathione in lymphocyte activation. I. Comparison of inhibitory effects of buthionine sulfoximine and 2-cyclohexene-1-one by nuclear size transformation. Journal of Immunology 135, 2740–2747.CrossRefGoogle ScholarPubMed
Herzenberg, LA, De Rosa, SC, Dubs, JG, Roederer, M, Anderson, MT, Ela, SW, Deresinski, SC & Herzenberg, LA (1997) Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences USA 94, 1967–1972.CrossRefGoogle ScholarPubMed
Hortin, GL, Landt, M & Powderly, WG (1994) Changes in plasma amino acid concentrations in response to HIV-1 infection. Clinical Chemistry 40, 785–789.CrossRefGoogle ScholarPubMed
Ishii, T, Sugita, Y & Bannai, S (1987) Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine. Journal of Cellular Physiology 133, 330–336.CrossRefGoogle ScholarPubMed
Jahoor, F, Jackson, A, Gazzard, B, Philips, G, Sharpstone, D, Frazer, ME & Heird, W (1999) Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. American Journal of Physiology 276, E205–E211.Google ScholarPubMed
Kinscherf, R, Fischbach, T, Mihm, S, Roth, S, Hohenhaus-Sievert, E, Weiss, C, Edler, L, Bärtsch, P & Dröge, W (1994) Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells. FASEB Journal 8, 448–451.CrossRefGoogle ScholarPubMed
Lim, J-S, Eck, H-P, Gmünder, H & Dröge, W (1992) Expression of increased immunogenicity by thiol releasing tumor variants. Cellular Immunology 140, 345–356.CrossRefGoogle ScholarPubMed
Los, M, Schenk, H, Hexel, K, Baeuerle, PA, Dröge, W & Schulze-Osthoff, K (1995) IL-2 gene expression and NF-κB activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO Journal 14, 3731–3740.CrossRefGoogle ScholarPubMed
Lubaszewska, S, Pastuszewska, B & Kielanowski, J (1973) Effect of methionine supplementation of a protein-free diet on the nitrogen excretion in rats and pigs. Tierphysiologie, Tierernährung und Futtormittelkunde 31, 120–128.CrossRefGoogle ScholarPubMed
Meister, A (1983) Selective modification of glutathione metabolism. Science 220, 471–477.CrossRefGoogle ScholarPubMed
Meister, A & Anderson, ME (1983) Glutathione. Annual Review of Biochemistry 52, 711–760.CrossRefGoogle ScholarPubMed
Meyer, M, Schreck, R & Baeuerle, PA (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 Journal 12, 2005–2015.CrossRefGoogle ScholarPubMed
Mihm, S, Ennen, J, Pessara, U, Kurth, R & Dröge, W (1991) Inhibition of HIV-1 replication and NF-κB activity by cysteine and cysteine derivatives. AIDS 5, 497–503.CrossRefGoogle ScholarPubMed
Nakamura, H, Nakamura, K & Yodoi, J (1997) Redox regulation of cellular activation. Annual Review of Immunology 15, 351–369.CrossRefGoogle ScholarPubMed
Okumura, J & Muramatsu, T (1978) Effect of dietary methionine and arginine on the excretion of nitrogen in cocks fed on a protein-free diet. Japanese Poultry Science 15, 69–73.CrossRefGoogle Scholar
Pacht, ER, Diaz, P, Clanton, T, Hart, J & Gadek, JE (1997) Alveolar fluid glutathione decreases in asymptomatic HIV-seropositive subjects over time. Chest 112, 785–788.CrossRefGoogle ScholarPubMed
Roederer, M, Staal, FJT, Osada, H & Herzenberg, LA (1991) CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as HIV infection progresses. International Immunology 3, 933–937.CrossRefGoogle ScholarPubMed
Roth, S & Dröge, W (1987) Regulation of T cell activation and T cell growth factor (TCGF) production by hydrogen peroxide. Cellular Immunology 108, 417–424.CrossRefGoogle Scholar
Roth, S & Dröge, W (1991) Regulation of interleukin-2 production, interleukin 2 mRNA expression and intracellular glutathione levels in ex vivo derived T lymphocytes by lactate. European Journal of Immunology 21, 1933–1937.CrossRefGoogle ScholarPubMed
Roth, S & Dröge, W (1994) Glutathione reverses the inhibition of T cell responses by superoptimal numbers of 'non- professional' antigen presenting cells. Cellular Immunology 155, 183–194.CrossRefGoogle Scholar
Schenk, H, Klein, M, Erdbrügger, W, Dröge, W & Schulze-Osthoff, K (1994) Distinct effects of thioredoxin and antioxidants on the activation of NFκB and AP-1. Proceedings of the National Academy of Sciences USA 91, 1672–1676.CrossRefGoogle Scholar
Schreck, R, Rieber, P & Baeuerle, PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NFκB transcription factor and HIV-1. EMBO Journal 10, 2247–2258.CrossRefGoogle Scholar
Staal, FJ, Ela, SW, Roederer, M, Anderson, MT, Herzenberg, LA & Herzenberg, LA (1992) Glutathione deficiency and human immunodeficiency virus infection. Lancet 339, 909–912.CrossRefGoogle ScholarPubMed
Walmsley, SL, Winn, LM, Harrosin, ML, Uetrecht, JP & Wells, PG (1997) Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS 11, 1689–1697.CrossRefGoogle ScholarPubMed
Webel, DM & Baker, DH (1999) Cystine is the first limiting amino acid for utilization of endogenous amino acids in chicks fed a protein-free diet. Nutrition Research 19, 569–577.CrossRefGoogle Scholar
Yoshida, A & Moritoki, K (1974) Nitrogen sparing action of methionine and threonine in rats receiving a protein-free diet. Nutrition Reports International 9, 159–168.Google Scholar