Hostname: page-component-5d59c44645-hb754 Total loading time: 0 Render date: 2024-02-23T09:18:10.466Z Has data issue: false hasContentIssue false

Zinc and the immune system

Published online by Cambridge University Press:  28 February 2007

Lothar Rink*
Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Ratzeburger Allee 160, D-23538 Lübeck, Germany
Corresponding Author: Dr Lothar Rink, fax +49 451 500 3069, email
Rights & Permissions [Opens in a new window]


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.

Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn. (1) The dietary intake and the resorption of Zn depends on the composition of the diet and also on age and disease status. (2) Zn is a cofactor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (3) Direct effects of Zn on the production, maturation and function of leucocytes. (4) Zn influences the function of immunostimulants used in the experimental systems. Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.

Meeting Report
Copyright © The Nutrition Society 2000


aCampo, C, Wellinghausen, N, Faber, C, Fischer, A & Rink, L (2000) Zinc inhibits the mixed lymphocyte culture. Biological Trace Element Research (In the Press).Google Scholar
Aicher, WK, Heer, AH, Trabandt, A, Bridges, SL Jr, Schroeder, HW Jr, Stransky, G, Gay, RE, Eibel, H, Peter, HH, Siebenlist, U, Koopman, WJ & Gay, S (1994) Overexpression of zinc-finger transcription factor z-225/Egr-1 in synoviocytes from rheumatoid arthritis patients. Journal of Immunology 152, 59405948.Google Scholar
Aicher, WK, Sakamoto, KM, Hack, A & Eibel, H (1999) Analysis of functional elements in the human Egr-1 gene promoter. Rheumatology International 8, 207214.Google Scholar
Allen, JI, Perri, RT, McClain, CJ & Kay, NE (1983) Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency. Journal of Laboratory and Clinical Medicine 102, 577589.Google Scholar
Andres, ME, Burger, C, Peral-Rubio, MJ, Battaglioli, E, Anderson, ME, Grimes, J, Dallman, J, Ballas, N & Mandel, G (1999) CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proceedings of the National Academy of Sciences USA 96, 98739878.Google Scholar
Antonucci, A, Di-Baldassarre, A, Di-Giacomo, F, Stuppia, L & Palka, G (1997) Detection of apoptosis in peripheral blood cells of 31 subjects affected by Down syndrome before and after zinc therapy. Ultrastructural Pathology 21, 449452.Google Scholar
Armstrong, RC, Kim, JG & Hudson, LD (1995) Expression of myelin transcription factor I (MyTI), a 'zinc-finger' DNA-binding protein, in developing oligodendrocytes. Glia 14, 303321.Google Scholar
Bach, JF (1981) The multi-faceted zinc dependency of the immune system. Immunology Today 4, 225227.Google Scholar
Bach, JF (1983) Thymulin (FTS-Zn). Clinics in Immunology and Allergy 3, 133150.Google Scholar
Balaban, N, Goldkorn, T, Nhan, RT, Dang, LB, Scott, S, Ridgley, RM, Rasooly, A, Wright, SC, Larrick, JW, Rasooly, R & Carlson, JR (1998) Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus. Science 280, 438440.Google Scholar
Balaban, N & Novick, RP (1995) Autocrine regulation of toxin synthesis by Staphylococcus aureus. Proceedings of the National Academy of Sciences USA 92, 16191623.Google Scholar
Bedwal, RS & Bahuguna, A (1994) Zinc, copper and selenium in reproduction. Experientia 50, 626640.Google Scholar
Bentley, PJ (1992) Influx of zinc by channel catfish (Ictalurus punctatus): uptake from external environmental solutions. Comparative Biochemistry and Physiology 101C, 215217.Google Scholar
Berger, NA & Skinner, M (1974) Characterization of lymphocyte transformation induced by zinc ions. Journal of Cellular Biology 61, 4555.Google Scholar
Bernatchez, C, Al-Daccak, R, Mayer, PE, Mehindate, K, Rink, L, Mecheri, S & Mourad, W (1997) Functional analysis of Mycoplasma arthritidis-derived mitogen interaction with class II molecules. Infection and Immunity 65, 20002005.Google Scholar
Bettger, WJ & O'Dell, BL (1993) Physiological roles of zinc in the plasma membrane of mammalian cells. Journal of Nutritional Biochemistry 4, 194207.Google Scholar
Bonomini, M, Di Paolo, B, De Risio, F, Niri, L, Klinkmann, H, Ivanowich, P & Albertazzi, A (1993) Effects of zinc supplementation in chronic haemodialysis patients. Nephrology Dialysis and Transplantation 8, 11661168.Google Scholar
Braunschweig, CL, Sowers, M, Kovacevich, DS, Hill, GM & August, DA (1997) Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. Journal of Nutrition 127, 7074.Google Scholar
Brewer, GJ, Aster, JC, Knutsen, CA & Kruckeberg, WC (1979) Zinc inhibition of calmodulin: a proposed molecular mechanism of zinc action on cellular functions. American Journal of Hematology 7, 5360.Google Scholar
Brewer, GJ & Bereza, UL (1982) Therapy of sickle cell anemia with membrane expander/calmodulin inhibitor classes of drugs. In Clinical, Biochemical, and Nutritional Aspects of Trace Elements, pp. 211220 [Prasad, AS, editor]. New York: Liss.Google Scholar
Brewer, GJ, Dick, RD, Yuzbasiyan-Gurkan, V, Johnson, V & Wang, Y (1994) Treatment of Wilson's disease with zinc. XIII: Therapy with zinc in presymptomatic patients from the time of diagnosis. Journal of Laboratory and Clinical Medicine 123, 849858.Google Scholar
Brewer, GJ & Yuzbasiyan-Gurkan, V (1992) Wilson disease. Medicine 71, 139164.Google Scholar
Brignola, C, Belloli, C, DeSimone, G, Evangelisti, A, Parente, R, Mancini, R, Innan, P, Mocchegiani, E, Fabris, N & Morini, MC (1993) Zinc supplementation restores plasma concentrations of zinc and thymulin in patients with Crohn's disease. Alimentary and Pharmacology and Therapeutics 7, 275280.Google Scholar
Brodersen, HP, Holtkamp, W, Larbig, D, Beckers, B, Thiery, J, Lautenschlager, J, Probst, HJ, Ropertz, S & Yavari, A (1995) Zinc supplementation and hepatitis B vaccination in chronic haemodialysis patients a multicentre study. Nephrology Dialysis Transplantation 10, 1780.Google Scholar
Bulgarini, D, Habetswallner, D, Boccoli, G, Montesoro, E, Camagna, A, Mastroberardino, G, Rosania, C, Testa, U & Peschle, C (1989) Zinc modulates the mitogenic activation of human peripheral blood lymphocytes. Annali dell Istituto Superiore di Sanita 25, 463470.Google Scholar
Cakman, I, Kirchner, H & Rink, L (1997) Zinc supplementation reconstitutes the production of interferon-α by leukocytes from elderly persons. Journal of Interferon and Cytokine Research 17, 469472.Google Scholar
Cakman, I, Rohwer, J, Schütz, RM, Kirchner, H & Rink, L (1996) Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mechanisms of Ageing and Development 87, 197209.Google Scholar
Chalaux, E, Lopez-Rovira, T, Rosa, JL, Pons, G, Boxer, LM, Batrons, R & Ventura, F (1999) A zinc-finger transcription factor induced by TGF-beta promotes apoptotic cell death in epithelial Mv1Lu cells. FEBS Letters 457, 478482.Google Scholar
Chandra, RK (1984) Excessive intake of zinc impairs immune responses. Journal of the American Medical Association 252, 14431446.Google Scholar
Chang, CC, Ye, BH, Chaganti, RS & Dalla-Favera, R (1996) BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proceedings of the National Academy of Sciences USA 93, 69476952.Google Scholar
Chavakis, T, May, AE, Preissner, KT & Kanse, SM (1999) Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and β2-integrins. Blood 93, 29762983.Google Scholar
Chesters, JK (1992) Trace elements–gene interactions. Nutrition Reviews 50, 217223.Google Scholar
Chvapil, M (1976) Effect of zinc on cells and biomembranes. Medical Clinics of North America 60, 799812.Google Scholar
Clohessy, PA & Golden, BE (1995) Calprotectin-mediated zinc chelation as a biostatic mechanism in host defense. Scandinavian Journal of Immunology 42, 551556.Google Scholar
Coleman, JE (1992 a) Zinc proteins: Enzymes, storage proteins, transcription factors and replication proteins. Annual Review of Biochemistry 16, 897946.Google Scholar
Coleman, JE (1992 b) Structure and mechanism of alkaline phosphatase. Annual Review of Biophysics and Biomolecular Structure 21, 441483.Google Scholar
Coto, JA, Hadden, EM, Sauro, M, Zorn, N & Hadden, JW (1992) Interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on T-lymphocyte proliferation and nuclear protein kinase C. Proceedings of the National Academy of Sciences USA 89, 77527756.Google Scholar
Crea, A, Guérin, V, Ortega, F & Hartemann, P (1990) Zinc et système immunitaire (Zinc and immune system). Annales de Medecine Interne 141, 447451.Google Scholar
Csermely, P, Szamel, M, Resch, K & Somogyi, J (1988) Zinc can increase the activity of protein kinase C and contributes to its binding to plasma membrane in T lymphocytes. Journal of Biological Chemistry 263, 64876490.Google Scholar
Cunningham-Rundles, S, Bockman, RS, Lin, A, Giardina, PV, Hilgartner, MW, Caldwell-Brown, D & Carter, DM (1980) Physiological and pharmacological effects of zinc on immune response. Annals of the New York Academy of Sciences 587, 113122.Google Scholar
De-Rinaldis, E, Pisaneschi, G, Camacho-Vanegas, O & Beccari, E (1998) The binding sites for Xenopus laevis FIII/YY1 in the first exon of L1 and L14 ribosomal protein genes are dispensable for promoter expression. European Journal of Biochemistry 255, 563569.Google Scholar
Deuel, TF, Guan, LS & Wang, ZY (1999) Wilms tumor gene product WT1 arrests macrophage differentiation of HL-60 cells through its zinc-finger domain. Biochemical and Biophysical Research Communications 254, 192196.Google Scholar
Dowd, PS, Kelleher, J & Guillou, PJ (1986) T-lymphocyte subsets and interleukin-2 production in zinc-deficient rats. British Journal of Nutrition 55, 5969.Google Scholar
Driessen, C, Hirv, K, Kirchner, H & Rink, L (1995 a) Divergent effects of zinc on different bacterial pathogenic agents. Journal of Infectious Diseases 171, 486489.Google Scholar
Driessen, C, Hirv, K, Kirchner, H & Rink, L (1995 b) Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology 84, 272277.Google Scholar
Driessen, C, Hirv, K, Rink, L & Kirchner, H (1994) Induction of cytokines by zinc ions in human peripheral blood mononuclear cells and separated monocytes. Lymphokine and Cytokine Research 13, 1520.Google Scholar
Driessen, C, Hirv, K, Wellinghausen, N, Kirchner, H & Rink, L (1995 c) Influence of serum on zinc, toxic shock syndrome toxin-1, and lipopolysaccharide-induced production of IFN-γ and IL-1β by human mononuclear cells. Journal of Leukocyte Biology 57, 904908.Google Scholar
Duchateau, J, Delespesse, G & Vereecke, P (1981) Influence of oral zinc supplementation on the lymphocyte response to mitogens of normal subjects. American Journal of Clinical Nutrition 34, 8893.Google Scholar
Easley, D, Krebs, N, Jefferson, M, Miller, L, Erskine, J, Accurso, F & Hambidge, KM (1998) Effect of pancreatic enzymes on zinc absorption in cystic fibrosis. Journal of Pediatric Gastroenterology and Nutrition 26, 136139.Google Scholar
Esmaeli, B, Burnstine, MA, Martonyi, CL, Sugar, A, Johnson, V & Brewer, GJ (1996) Regression of Kayser-Fleischer rings during oral zinc therapy: correlation with systemic manifestation of WD. Cornea 15, 582588.Google Scholar
Favier, A & Favier, M (1990) Consequences des deficits en zinc durant la grossesse pour la mère et le nouveau-né (Consequences of zinc deficits during pregnancy for the mother and newborn). Revue Française de Gynecologie et d'Obstetrique 85, 1327.Google Scholar
Favier, AE (1992) The role of zinc in reproduction. Hormonal mechanisms. Biological Trace Element Research 32, 363382.Google Scholar
Feduchi, E, Gallego, MI & Lazo, PA (1994) The human zinc-finger protein-7 gene is located 90 kb 3> of MYC and is not expressed in Burkitt lymphoma cell lines. International Journal of Cancer 58, 855859.+of+MYC+and+is+not+expressed+in+Burkitt+lymphoma+cell+lines.+International+Journal+of+Cancer+58,+855–859.>Google Scholar
Flieger, D, Riethmüller, G & Ziegler-Heitbrock, HWL (1990) Zn2+ inhibits both tumor necrosis factor-mediated DNA fragmentation and cytolysis. International Journal of Cancer 44, 315319.Google Scholar
Fraker, PJ, Gershwin, ME, Good, RA & Prasad, A (1986) Interrelationships between zinc and immune functions. Federation Proceedings 45, 14741479.Google Scholar
Fraker, PJ, Osati-Ashtiani, F, Wagner, MA & King, LE (1995) Possible roles for glucocorticoids and apoptosis in the suppression of lymphopoiesis during zinc deficiency: a review. Journal of the American College of Nutrition 14, 1117.Google Scholar
Fraser, JD, Urban, RG, Strominger, JL & Robinson, H (1992) Zinc regulates the function of two superantigens. Proceedings of the National Academy of Sciences USA 89, 55075511.Google Scholar
Fukamachi, Y, Karasaki, Y, Sugiura, T, Itoh, H, Yamamura, K & Higashi, K (1998) Zinc suppresses apoptosis of U937 cells induced by hydrogen peroxide through an increase of the Bcl-2/ Bax ratio. Biochemical and Biophysical Research Communications 246, 364369.Google Scholar
Gearhart, DA, Neafsey, EJ & Collins, MA (1997) Characterization of brain beta-carboline-2-N-methyltransferase, an enzyme that may play a role in idiopathic Parkinson's disease. Neurochemical Research 22, 113121.Google Scholar
German Society of Nutrition (1995) Ausschuß Nahrungsbedarf der DGE Zufuhrempfehlungen und Nährstoffbedarf. Teil II: Vergleich der Vorschläge von SCF/EC mit den Empfehlungen der DGE (Dietary requirements committee of DGE recommended intakes and nutrient requirements. Part 2. Comparison of proposals of SCF/EC with the recommendations of DGE). Ernährungsumschau 42, 410.Google Scholar
Goode, HF, Kelleher, J & Walker, BE (1989) Zinc concentrations in pure populations of peripheral blood neutrophils, lymphocytes and monocytes. Annals of Clinical Biochemistry 26, 8995.Google Scholar
Greskas, D, Alivanis, P, Kotzadamis, N, Kiriazopoulos, M & Tourkantonis, A (1992) Influenza vaccination in chronic hemodialysis patients. The effect of zinc supplementation. Renal Failure 14, 575578.Google Scholar
Groman, N & Judge, K (1979) Effect of metal ions on diphteria toxin production. Infection and Immunity 26, 10651070.Google Scholar
Hadden, JW (1995) The treatment of zinc is an immunotherapy. International Journal of Immunopharmacology 17, 697701.Google Scholar
Heldin, CH (1995) Dimerization of cell surface receptors in signal transduction. Cell 80, 213223.Google Scholar
Heng, MK, Song, MK & Heng, MCY (1993) Reciprocity between tissue calmodulin and cAMP levels: modulation by excess zinc. British Journal of Dermatology 129, 280285.Google Scholar
Hogstrand, C, Verbost, PM, Bonga, SE & Wood, CM (1996) Mechanisms of zinc uptake in gills of freshwater rainbow trout: interplay with calcium transport. American Journal of Physiology 270, R1141R1147.Google Scholar
Humeny, A, Bokenkamp, D & Thole, HH (1999) The HDQVH-motif in domain E of the estradiol receptor alpha is responsible for zinc-binding and zinc-induced hormone release. Molecular and Cellular Endocrinology 153, 7178.Google Scholar
Hynes, M, Stone, DM, Dowd, M, Pitts-Meek, S, Goddard, A, Gurney, A & Rosenthal, A (1997) Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19, 1526.Google Scholar
Ishido, M, Suzuki, T, Adachi, T & Kunimoto, M (1999) Zinc stimulates DNA synthesis during its antiapoptotic action independently with increments of an antiapoptotic protein, Bcl-2, in porcine kidney LLC-PK cells. Journal of Pharmacology and Experimental Therapeutics 290, 923928.Google Scholar
James, K (1990) Interaction between cytokines and α2-macroglobulin. Immunology Today 11, 163166.Google Scholar
Jameson, S (1993) Zinc status in pregnancy: the effect of zinc therapy on perinatal mortality, prematurity, and placental ablation. Annals of the New York Academy of Sciences 678, 178192.Google Scholar
Jiang, S, Chow, SC, McCabe, MJ Jr & Orrenius, S (1995) Lack of Ca2+ involvement in thymocyte apoptosis induced by chelation of intracellular Zn2+. Laboratory Investigation 73, 111117.Google Scholar
Kawahara, M, Arispe, N, Kuroda, Y, Rojas, E (1997) Alzheimer's disease amyloid beta-protein forms Zn(2+)-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons. Biophysical Journal 73, 6775.Google Scholar
Keen, CL & Gershwin, ME (1990) Zinc deficiency and immune function. Annual Review of Nutrition 10, 415431.Google Scholar
Kim, J, Urban, RG, Strominger, JL & Wiley, DC (1994) Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science 266, 18701878.Google Scholar
Kirchner, H & Rühl, H (1970) Stimulation of human peripheral lymphocytes by Zn2+ in vitro. Experimental Cell Research 61, 229230.Google Scholar
Klaiman, AP, Victery, W, Kluger, MJ & Vander, AJ (1981) Urinary excretion of zinc and iron following acute injection of dead bacteria in dog. Proceedings of the Society for Experimental Biology and Medicine 167, 165171.Google Scholar
Klosterhalfen, B, Töns, C, Hauptmann, S, Tietze, L, Offner, FA, Küpper, W & Kirkpatrick, CJ (1996) Influence of heat shock protein 70 and metallothionein induction by zinc-bis-(DL-hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia. Biochemical Pharmacology 52, 12011210.Google Scholar
Krasovec, M & Frenk, E (1996) Acrodermatitis enteropathica secondary to Crohn's disease. Dermatology 193, 361363.Google Scholar
Kreft, B, Fischer, A, Krüger, S, Sack, K, Kirchner, H & Rink, L (2000) The impaired immune response to diphtheria vaccination in elderly chronic hemodialysis patients is related to zinc deficiency. Biogerontology 1, 6166.Google Scholar
Kruse-Jarres, JD (1989) The significance of zinc for humoral and cellular immunity. Journal of Trace Elements and Electrolytes in Health and Diseases 3, 18.Google Scholar
Lighart, GJ, Coberand, JX, Fournier, C, Galanaud, P, Hijmans, W, Kennes, B, Müller-Hermelink, HK & Steinmann, GG (1984) Admission criteria for immunogerontological studies in man: The Senieur Protocol. Mechanisms of Ageing and Development 28, 4755.Google Scholar
Lin, H, Zhu, YJ & Lal, R (1999) Amyloid beta protein (1–40) forms calcium permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38, 1118911196.Google Scholar
Maret, W (1998) The glutathione redox state and zinc mobilization from metallothionein and other proteins with zinc-sulfur coordination sites. In Glutathione in the Nervous System, pp. 257273 [Shaw, CA, editor]. Philadelphia, PA: Taylor & Francis.Google Scholar
Maret, W, Jacob, C, Vallee, BL & Fischer, EH (1999) Inhibitory sites in enzymes: Zinc removal and reactivation by thionein. Proceedings of the National Academy of Sciences USA 96, 19361940.Google Scholar
Mills, CF (1989) Zinc in Human Biology. Human Nutrition Reviews. London: Springer Verlag.Google Scholar
Mocchegiani, E, Santarelli, L, Muzzioli, M & Fabris, N (1995 a) Reversibility of the thymic involution and of age-related peripheral immune dysfunction by zinc supplementation in old mice. International Journal of Immunopharmacology 17, 703718.Google Scholar
Mocchegiani, E, Veccia, S, Ancarani, F, Scalise, G & Fabris, N (1995 b) Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. International Journal of Immunopharmacology 17, 719727.Google Scholar
Mossad, SB, Macknin, ML, Medendorp, SV & Mason, P (1996) Zinc gluconate lozenges for treating the common cold. Annals of Internal Medicine 125, 8188.Google Scholar
Muraosa, Y, Takahashi, K, Yoshizawa, M & Shibahara, S (1996) cDNA cloning of a novel protein containing two zinc-finger domains that may function as a transcription factor for the human heme-oxygenase-1 gene. European Journal of Biochemistry 23, 471479.Google Scholar
Murthy, ARK, Lehrer, RI, Harwig, SSL & Miyasaki, KT (1993) In vitro candidastatic properties of the human neutrophil calprotectin complex. Journal of Immunology 151, 62916301.Google Scholar
Myung, SJ, Yang, SK, Jung, HY, Jung, SA, Kang, GH, Ha, HK, Hong, WS & Min, Y (1998) Zinc deficiency manifested by dermatitis and visual dysfunction in a patient with Crohn's disease. Journal of Gastroenterology 33, 876879.Google Scholar
Najim, RA, Sharquie, KE & Farjou, IB (1998) Zinc sulphate in the treatment of cutaneous leishmaniasis: an in vitro and animal study. Memorias do Instituto Oswaldo Cruz 93, 831837.Google Scholar
Nakayama, H, Scott, IC & Cross, JC (1998) The transition to endoreduplication in trophoblast giant cells is regulated by the mSNA zinc finger transcription factor. Developmental Biology 199, 150163.Google Scholar
Neldner, KH & Hambidge, KM (1975) Zinc therapy in acrodermatitis enteropathica. New England Journal of Medicine 292, 879882.Google Scholar
Neves, I Jr, Bertho, AL, Veloso, VG, Nascimento, DV, Campos-Mello, DL & Morgado, MG (1998) Improvement of the lymphoproliferative immune response and apoptosis inhibition upon in vitro treatment with zinc of peripheral blood mononuclear cells (PBMC) from HIV+ individuals. Clinical and Experimental Immunology 111, 264268.Google Scholar
Nowak, G (1998) Alterations in zinc homeostasis in depression and antidepressant therapy. Polish Journal of Pharmacology 50, 14.Google Scholar
Nowak, G & Schlegel-Zawadzka, M (1999) Alterations in serum and brain trace element levels after antidepressant treatment: part I. Zinc. Biological Trace Element Research 67, 8592.Google Scholar
O'Halloran, TV (1993) Transition metals in control of gene expression. Science 261, 715725.Google Scholar
Osati-Ashtiani, F, King, LE & Fraker, PJ (1998) Variance in the resistance of murine early bone marrow B cells to a deficiency in zinc. Immunology 94, 94100.Google Scholar
Palmiter, RD & Findley, SD (1995) Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO Journal 14, 639649.Google Scholar
Palmiter, RD, Cole, TB & Findley, SD (1996 a) ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO Journal 15, 17841791.Google Scholar
Palmiter, RD, Cole, TB, Quaife, CJ & Findley, SD (1996 b) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proceedings of the National Academy of Sciences USA 93, 1493414939.Google Scholar
Patterson, WP, Winkelmann, M & Perry, MC (1985) Zinc-induced copper deficiency: megamineral sideroblastic anemia. Annals of Internal Medicine 103, 385386.Google Scholar
Pavletich, NP & Pabo, CO (1993) Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science 261, 17011707.Google Scholar
Philipsen, S & Suske, G (1999) A tale of three fingers: the family of mammalian Sp/XKLF transcription factors. Nucleic Acids Research 27, 29913000.Google Scholar
Phillips, JL & Azari, P (1974) Zinc transferrin: Enhancement of nucleic acid synthesis in phytohemagglutinin-stimulated human lymphocytes. Cellular Immunology 10, 3137.Google Scholar
Pohl, E, Qui, X, Must, LM, Holmes, RK & Hol, WG (1997) Comparison of high-resolution structures of the diphteria toxin repressor in complex with cobalt and zinc at the cation-anion binding site. Protein Science 6, 11141118.Google Scholar
Porter, KG, McMaster, D, Elmes, ME & Love, AH (1977) Anaemia and low serum-copper during zinc therapy. Lancet ii, 774.Google Scholar
Prasad, AS (1995) Zinc: an overview. Nutrition 11, 9399.Google Scholar
Prasad, AS (1996) Zinc deficiency in women, infants and children. Journal of the American College of Nutrition 15, 113120.Google Scholar
Prasad, AS, Beck, FW, Kaplan, J, Chandrasekar, PH, Ortega, J, Fitzgerald, JT & Swerdlow, P (1999) Effect of zinc supplementation on incidence of infections and hospital admission in sickle cell disease (SCD). American Journal of Hematology 61, 194202.Google Scholar
Prasad, AS, Miaie, A Jr, Farid, Z, Schulert, A & Sandstead, HH (1963) Zinc metabolism in patients with the syndrome of iron deficiency, hypogonadism and dwarfism. Journal of Laboratory and Clinical Medicine 83, 537549.Google Scholar
Provinciali, M, Montenovo, A, Di-Stefano, G, Colombo, M, Daghetta, L, Cairati, M, Veroni, C, Cassino, R, Della-Torre, F & Fabris, N (1998) Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial. Age and Ageing 27, 715722.Google Scholar
Rajagopalan, S, Winter, CC, Wagtmann, N & Long, EO (1995) The Ig-related killer cell inhibitory receptor binds zinc and requires zinc for recognition of HLA-C on target cells. Journal of Immunology 155, 41434146.Google Scholar
Raulin, J (1869) Etudes chimique sur la vegetation (Chemical studies on plants). Annales des Sciences Naturelles Botanique et Biologie Vegetale 11, 293299.Google Scholar
Rawer, P, Willems, WR, Breidenbach, T, Guttmann, W, Pabst, W & Schutterle, G (1987) Seroconversion rate hepatitis B vaccination, hemodialysis, and zinc supplementation. Kidney International 22S, 149152.Google Scholar
Reinhold, D, Ansorge, S & Grüngreiff, K (1999) Immunobiology of zinc and zinc therapy. Immunology Today 20, 102.Google Scholar
Rink, L & Kirchner, H (1999) Reply to Reinhold et al. Immunology Today 20, 102103.Google Scholar
Rühl, H & Kirchner, H (1978) Monocyte-dependent stimulation of human T cells by zinc. Clinical and Experimental Immunology 32, 484488.Google Scholar
Rühl, H, Kirchner, H & Borchert, G (1971) Kinetics of the Zn2+-stimulation of human peripheral lymphocytes in vitro. Proceedings of the Society for Experimental Biology and Medicine 137, 10891092.Google Scholar
Safie-Garabedian, B, Ahmed, K, Khamashta, MA, Taub, NA & Hughes, GRV (1993) Thymulin modulates cytokine release by peripheral blood mononuclear cells: a comparison between healthy volunteers and patients with systemic lupus erythematodes. International Archives of Allergy and Immunology 101, 126131.Google Scholar
Saha, AR, Hadden, EM & Hadden, JW (1995) Zinc induces thymulin secretion from human thymic epithelial cells in vitro and augments splenocyte and thymocyte responses in vivo. International Journal of Immunopharmacology 17, 729733.Google Scholar
Sakai, Y, Nakagawa, R, Sato, R & Maeda, M (1998) Selection of DNA binding sites for human transcriptional regulator GATA-6. Biochemical and Biophysical Research Communications 250, 682688.Google Scholar
Salas, M & Kirchner, H (1987) Induction of interferon-γ in human leukocyte cultures stimulated by Zn2+. Clinical Immunology and Immunopathology 45, 139142.Google Scholar
Sampson, B, Kovar, IZ, Rauscher, A, Fairweather-Tait, S, Beattie, J, McArdle, HJ, Ahmed, R & Green, C (1997) A case of hyperzincemia with functional zinc depletion: a new disorder? Pediatric Research 42, 219225.Google Scholar
Sandstead, HH, Henriksen, LK, Greger, JL, Prasad, AS & Good, RA (1982) Zinc nutriture in the elderly in relation to taste acuity, immune response, and wound healing. American Journal of Clinical Nutrition 36, 10461059.Google Scholar
Schoenmakers, E, Alen, P, Verrijdt, G, Peeters, B, Verhoeven, G, Rombauts, W & Claessens, F (1999) Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains. Biochemical Journal 341, 515521.Google Scholar
Scholl, TO, Hediger, ML, Schall, JI, Fischer, RL & Khoo, CS (1993) Low zinc intake during pregnancy: its association with preterm and very preterm delivery. American Journal of Epidemiology 137, 11151124.Google Scholar
Scott, BJ & Bradwell, AR (1983) Identification of the serum binding proteins for iron, zinc, cadmium, nickel and calcium. Clinical Chemistry 29, 629633.Google Scholar
Scuderi, P (1990) Differential effects of copper and zinc on human peripheral blood monocyte cytokine secretion. Cellular Immunology 126, 391405.Google Scholar
Shimizu, N, Yamauchi, Y & Aoki, T (1999) Treatment and management of Wilson's disease. Pediatrics International 41, 419422.Google Scholar
Simkin, PA (1976) Oral zinc sulphate in rheumatoid arthritis. Lancet ii, 539542.Google Scholar
Skamoto, A, Omirulleh, S, Nakayama, T & Iwabuchi, M (1996) A zinc-finger-type transcription factor WZF-1 that binds to a novel cis-acting element of histone gene promoters represses its own promoter. Plant and Cellular Physiology 37, 557562.Google Scholar
Sohnle, PG, Collins-Lech, C & Wiessner, JH (1991) The zinc-reversible antimicrobial activity of neutrophil lysates and abscess fluid supernatants. Journal of Infectious Diseases 164, 137142.Google Scholar
Song, A, Chen, YF, Thamatrakoln, K, Storm, TA & Krensky, AM (1999) RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes. Immunity 10, 93103.Google Scholar
Sood, SM, Wu, MX, Hill, KA & Slattery, CW (1999) Characterization of zinc-depleted alanyl-tRNA synthetase from Escherichia coli: role of zinc. Archives of Biochemistry and Biophysics 368, 380384.Google Scholar
Sturniolo, GC, Mestriner, C, Irato, P, Albergoni, V, Longo, G & D'Inca, R (1999) Zinc therapy increases duodenal concentrations of metallothionein and iron in Wilson's disease patients. American Journal of Gastroenterology 94, 334338.Google Scholar
Sundström, M, Abrahamsen, L, Antonsson, P, Mehindate, K, Mourad, W & Dohlsten, M (1996) The crystal structure of staphylococcal enterotoxin type D reveals Zn2+ mediated homodimerization. EMBO Journal 15, 68326840.Google Scholar
Tanaka, Y, Shiozawa, S, Morimoto, I & Fujita, T (1989) Zinc inhibits pokeweed mitogen-induced development of immunoglobulin-secreting cells through augmentation of both CD4 and CD8 cells. International Journal of Immunopharmacology 11, 673679.Google Scholar
Taylor, GA & Blackshear, PJ (1995) Zinc inhibits turnover of labile mRNAs in intact cells. Journal of Cellular Physiology 162, 378387.Google Scholar
The Finnish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. Nature Genetics 17, 399403.Google Scholar
Tierno, PM Jr & Hanna, BA (1985) In vitro amplification of toxic shock syndrome toxin-1 by intravaginal devices. Contraception 31, 185194.Google Scholar
Todd, WK, Elvelym, A & Hart, EB (1934) Zinc in the nutrition of the rat. American Journal of Physiology 107, 146156.Google Scholar
Trubiani, O, Antonucci, A, Palka, G & Di-Primio, R (1996) Programmed cell death of peripheral myeloid precursor cells in Down patients: effect of zinc therapy. Ultrastructural Pathology 20, 457462.Google Scholar
Tsuda, M, Imaizumi, K, Katayama, T, Kitagawa, K, Wanaka, A, Tohyama, M & Takagi, T (1997) Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil. Journal of Neuroscience 17, 66786684.Google Scholar
Turk, S, Bozfakioglu, S, Ecder, ST, Kahraman, T, Gurel, N, Erkoc, , Aysuna, N, Turkmen, A, Bekiroglu, N & Ark, E (1998) Effects of zinc supplementation on the immune system and on antibody response to multivalent influenza vaccine in hemodialysis patients. International Journal of Artificial Organs 21, 274278.Google Scholar
Turner, J & Crossley, M (1998) Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO Journal 17, 51295140.Google Scholar
Umezawa, K, Nakazawa, K, Uchihata, Y & Otsuka, M (1999) Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells. Advances in Enzyme Regulation 39, 145156.Google Scholar
Valberg, LS, Flanagan, PR & Chamberlain, MJ (1984) Effect of iron, tin and copper on zinc absorption in humans. American Journal of Clinical Nutrition 40, 536541.Google Scholar
Vallee, BL & Falchuk, KH (1993) The biochemical basis of zinc physiology. Physiological Reviews 73, 79118.Google Scholar
Varadinova, TL, Bontchev, PR, Nachev, CK, Shishkov, SA, Strachilov, D, Paskalev, Z, Toutekova, A & Panteva, M (1993) Mode of action of Zn-complexes on herpes simplex virus type 1 infection in vitro. Journal of Chemotherapy 5, 39.Google Scholar
Villiers, MB, Gabert, FM, Jacquier, MR & Colomb, MG (1993) Involvement of the Zn-binding region of the tetanus toxin in B and T recognition. Influence of Zn fixation. Molecular Immunology 30, 129136.Google Scholar
Warner, GL & Lawrence, DA (1986) Stimulation of murine lymphocyte response by cations. Cellullar Immunology 101, 425439.Google Scholar
Weiss, G, Wachter, H & Fuchs, D (1995) Linkage of cell-mediated immunity to iron metabolism. Immunology Today 16, 495500.Google Scholar
Weiss, G, Widner, B, Zoller, H & Fuchs, D (1998) The immunobiology of zinc and the kidney. Immunology Today 19, 193.Google Scholar
Wellinghausen, N, Driessen, C & Rink, L (1996 a) Stimulation of human peripheral blood mononuclear cells by zinc and related cations. Cytokine 18, 767771.Google Scholar
Wellinghausen, N, Fischer, A, Kirchner, H & Rink, L (1996 b) Interaction of zinc ions with human peripheral blood mononuclear cells. Cellular Immunology 171, 255261.Google Scholar
Wellinghausen, N, Kern, WV, Jöchle, W & Kern, P (2000) Zinc serum level in human deficiency virus infected patients in relation to immunological status. Biological Trace Element Research 73, 7989.Google Scholar
Wellinghausen, N, Kirchner, H & Rink, L (1997 a) The immunobiology of zinc. Immunology Today 18, 519521.Google Scholar
Wellinghausen, N, Martin, M & Rink, L (1997 b) Zinc inhibits IL-1 dependent T cell stimulation. European Journal of Immunology 27, 25292535.Google Scholar
Wellinghausen, N, Schromm, AB, Seydel, U, Brandenburg, K, Luhm, J, Kirchner, H & Rink, L (1996 c) Zinc enhances lipopolysaccharide-induced monokine secretion by a fluidity change of lipopolysaccharide. Journal of Immunology 157, 31393145.Google Scholar
Williams, AJ, Khachigian, LM, Shows, T & Collins, T (1995) Isolation and characterization of a novel zinc-finger protein with transcription repressor activity. Journal of Biological Chemistry 270, 2214322152.Google Scholar
Worwag, M, Classen, HG & Schumacher, E (1999) Prevalence of magnesium and zinc in nursing home residents in Germany. Magnesium Research 12, 181189.Google Scholar
Wright, SD & Kolesnick, RN (1995) Does endotoxin stimulate cells by mimicking ceramide? Immunology Today 16, 297302.Google Scholar
Yamagata, K, Kaufmann, WE, Lanahan, A, Papapavlou, M, Barnes, CA, Andreasson, KI & Worley, PF (1994) Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. Learning and Memory 1, 140152.Google Scholar
Yang, XW, Zhong, R & Heintz, N (1996) Granule cell specification in the developing mouse brain as defined by expression of the zinc finger transcription factor RU49. Development 122, 555566.Google Scholar
Yuzbasiyan-Gurkan, VA, Brewer, GJ, Vander, AJ, Guenter, MJ & Prasad, AS (1989) Net renal tubular reabsorption of zinc in healthy man and impaired handling in sickle cell anemia. American Journal of Hematology 31, 8790.Google Scholar
Zalewski, PD & Forbes, IJ (1993) Intracellular zinc and the regulation of apoptosis. In Programmed Cell Death: The Cellular and Molecular Biology of Apoptosis, pp. 7385[Laviri, M and Watters, D, editors\. Melbourne: Harword Academic Press.Google Scholar
Ziegler, EE, Serfass, RE, Nelson, SE, Figueroa-Colon, R, Edwards, BB, Houk, RS & Thompson, JJ (1989) Effect of low zinc intake on absorption and excretion of zinc by infants studied with 70Zn as extrinsic tag. Journal of Nutrition 119, 16471653.Google Scholar
Zoli, A, Altomonte, L, Caricchio, R, Gaossi, A, Mirone, L, Ruffini, MP & Magaro, M (1998) Serum zinc and copper in active rheumatoid arthritis: correlation with interleukin 1 beta and tumour necrosis factor alpha. Clinical Rheumatology 17, 378382.Google Scholar