Advertisement

Molecular Medicine

, Volume 14, Issue 5–6, pp 353–357 | Cite as

Zinc in Human Health: Effect of Zinc on Immune Cells

  • Ananda S. Prasad
Review Article

Abstract

Although the essentiality of zinc for plants and animals has been known for many decades, the essentiality of zinc for humans was recognized only 40 years ago in the Middle East. The zinc-deficient patients had severe immune dysfunctions, inasmuch as they died of intercurrent infections by the time they were 25 years of age. In our studies in an experimental human model of zinc deficiency, we documented decreased serum testosterone level, oligospermia, severe immune dysfunctions mainly affecting T helper cells, hyperammonemia, neurosensory disorders, and decreased lean body mass. It appears that zinc deficiency is prevalent in the developing world and as many as two billion subjects may be growth retarded due to zinc deficiency. Besides growth retardation and immune dysfunctions, cognitive impairment due to zinc deficiency also has been reported recently. Our studies in the cell culture models showed that the activation of many zinc-dependent enzymes and transcription factors were adversely affected due to zinc deficiency. In HUT-78 (T helper 0 (Th0) cell line), we showed that a decrease in gene expression of interleukin-2 (IL-2) and IL-2 receptor α (IL-2Rα) were due to decreased activation of nuclear factor-κB (NF-κB) in zinc deficient cells. Decreased NF-κB activation in HUT-78 due to zinc deficiency was due to decreased binding of NF-κB to DNA, decreased level of NF-κB p105 (the precursor of NF-κB p50) mRNA, decreased κB inhibitory protein (IκB) phosphorylation, and decreased Iκκ. These effects of zinc were cell specific. Zinc also is an antioxidant and has anti-inflammatory actions. The therapeutic roles of zinc in acute infantile diarrhea, acrodermatitis enteropathica, prevention of blindness in patients with age-related macular degeneration, and treatment of common cold with zinc have been reported. In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-κB activation, leading to decreased gene expression and generation of tumor necrosis factor-α (TNF-α), IL-1β, and IL-8. We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines.

Notes

Acknowledgments

Grant support for this work was provided in part by NIH grant 5 RO1 A150698-04 and Labcatal Laboratories, Paris, France.

References

  1. 1.
    Raulin, J. (1869) Chemical studies on vegetation [in French]. Ann. Sci. Nat. 11:93–9.Google Scholar
  2. 2.
    Todd WR, Elvehjem CA, Hart EB. (1934) Zinc in the nutrition of the rat. Am. J. Physiol. 107:146–56.Google Scholar
  3. 3.
    Prasad AS, Halsted JA, Nadimi M. (1961) Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am. J. Med. 31:532–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Prasad AS et al. (1963) Zinc metabolism in patients with the syndrome of iron deficiency anemia, hypogonadism and dwarfism. J. Lab. Clin. Med. 61:537–49.PubMedGoogle Scholar
  5. 5.
    Cavdar AO et al. (1983) Geophagia in Turkey: Iron and zinc deficiency, iron and zinc absorption studies and response to treatment with zinc in geophagia cases. In Prasad AS, Cavdar AO, Brewer GJ, Aggett PJ [eds]. Zinc deficiency in human subjects, Alan R. Liss Inc, New York. p.71–97.Google Scholar
  6. 6.
    Prasad AS. (1993) Biochemistry of Zinc. Plenum Press, New York.CrossRefGoogle Scholar
  7. 7.
    Prasad AS et al. (1988) Serum thymulin in human zinc deficiency. J. Clin. Invest. 82:1202–10.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Beck FWJ et al. (1997) Decreased expression of CD73 (ecto-5′-nucleotidase in the CD8+ subset is associated with zinc deficiency in human patients. J. Lab. Clin. Med. 130:147–56.CrossRefPubMedGoogle Scholar
  9. 9.
    Beck FWJ et al. (1997) Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am. J. Physiol. 272:E1002–7.PubMedGoogle Scholar
  10. 10.
    Shankar AH, Prasad AS. (1998) Zinc and immune function: the biological basis of altered resistance to infection. Am. J. Clin. Nutr. 68(suppl):447S–63S.CrossRefGoogle Scholar
  11. 11.
    Sazawal S et al. (1995) Zinc supplementation in young children with acute diarrhea in India. N. Engl. J. Med. 333:839–44.CrossRefPubMedGoogle Scholar
  12. 12.
    Sazawal S et al. (1998) Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double blind controlled trials. Pediatrics. 102:1–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Prasad AS et al. (1999) Effect of zinc supplementation on incidence of infections and hospital admissions in sickle disease (SCD). Am. J. Hematol. 61:194–202.CrossRefPubMedGoogle Scholar
  14. 14.
    Prasad AS et al. (2007) Zinc supplementation decreases incidence of infections in the elderly: Effect of zinc on generation of cytokines and oxidative stress. Am. J. Clin. Nutr. 85:837–44.CrossRefPubMedGoogle Scholar
  15. 15.
    Prasad AS et al. (2001) Zinc activates NF-κB in HUT-78 cells. J. Lab. Clin Med. 138:250–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Serfling E, Avots A, Neumann M. (1995) The architecture of the interleukin-2 promoter: a reflection of T-lymphocyte activation. Biochem. Biophys. Acta. 1263:181–200.PubMedGoogle Scholar
  17. 17.
    Arima N et al. (1998) IL-2 induced growth of CD8+ T cell prolymphocytic leukemia cells mediated by NF-κB induction and IL-2 receptor a expression. Leuk. Res. 22:265–73.CrossRefPubMedGoogle Scholar
  18. 18.
    Hatakeyama M et al. (1989) Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA’s. Science. 244:551–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Prasad AS, Bao B, Beck FWJ, Sarkar FH. (2002) Zinc enhances the expression of interleukin-2 and interleukin-2 receptors in HUT-78 cells by way of NF-κB activation. J. Lab. Clin. Med. 140:272–89.CrossRefPubMedGoogle Scholar
  20. 20.
    Castro L, Freeman BA. (2001) Reactive oxygen species in human health and disease. Nutrition. 17:161–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Davis JN et al. (2001) Soy isoflavone supplementation in healthy men prevents NF-κB activation by TNF-α in blood lymphocytes. Free Radic. Biol. Med. 30:1293–302.CrossRefPubMedGoogle Scholar
  22. 22.
    Lachance PA, Nakat Z, Jeong W. (2001) Antioxidants: An integrative approach. Nutrition. 17:835–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Ozaki Y, Ohashi T, Kume S. (1987) Potentiation of neutrophil function by recombinant DNA-produced interleukin-1α J. Leukoc. Biol. 42:621–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Berkow RL et al. (1987) Enhancement of neutrophil superoxide production by pre-incubation with recombinant human tumor necrosis factor. J. Immunol. 139:3783–91.PubMedGoogle Scholar
  25. 25.
    Uzzo RG et al. (2002) Zinc inhibits nuclear factor-κB activation and sensitizes prostate cancer cells to cytotoxic agents. Clin. Can. Res. 8:3579–83.Google Scholar
  26. 26.
    Kim CH et al. (1999) Pyrithione, a zinc ionophore, inhibits NF-kappaB activation. Biochem. Biophys. Res. Comm. 259:505–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Ho E et al. (2001) Dietary zinc supplementation inhibits NF-kappa B activation and protects against chemically induced diabetes in CD1 mice. Exp. Biol. Med. 226:103–11.CrossRefGoogle Scholar
  28. 28.
    Otsu K, Ikeda Y, Fujii J. (2004) Accumulation of manganese superoxide dismutase under metaldepleted conditions: proposed role for zinc ions in cellular redox balance. Biochem. J. 377:241–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Opipari Jr. AW, Boguski MS, Dixit VM. (1990) The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J. Biol. Chem. 265:14705–8.PubMedGoogle Scholar
  30. 30.
    Krikos A, Laherty CD, Dixit VM. (1992) Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by κB elements. J. Biol. Chem. 267:17971–6.PubMedGoogle Scholar
  31. 31.
    Heyninck K, Beyaert R. (1999) The cytokine-inducible zinc finger protein A20 inhibits IL-1 induced NF-κB activation at the level of TRAF6. FEBS Lett. 442:147–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Jaattela M et al. (1996) A20 zinc finger protein inhibits TNF and IL-1 signaling. J. Immun. 156:1166–73.PubMedGoogle Scholar
  33. 33.
    Song HY, Rothe M, Goeddel DV. (1996) The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-κB activation. Proc. Natl. Acad. Sci. U. S. A. 93:6721–5.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Prasad AS et al. (2004) Anti-oxidant effect of zinc in humans. Free Radic. Biol. Med. 37:1182–90.CrossRefPubMedGoogle Scholar
  35. 35.
    Tewari M et al. (1995) Lymphoid expression and regulation of A20, an inhibitor of programmed cell death. J. Immunol. 154:1699–706.PubMedGoogle Scholar
  36. 36.
    Fraker PJ, King LE. (2004) Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24:277–98.CrossRefPubMedGoogle Scholar
  37. 37.
    Age-Related Eye Disease Study Research Group (AREDS Report No.8). (2001) A randomized, placebo controlled, clinical trial of high-dose supplemented with vitamins C and E, beta-carotene, for age-related macular degeneration and vision loss. Arch. Ophthalmol. 119:1417–36.CrossRefGoogle Scholar
  38. 38.
    AREDS Report No.13. (2004) Association of mortality with ocular disorders and an intervention of high dose anti-oxidants and zinc in the age-related eye disease study. Arch. Ophthalmol. 122:716–26.CrossRefGoogle Scholar
  39. 39.
    Faber C, Gabriel P, Ibs KH, Rink L. (2004) Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response. Bone Marrow Transplant. 33:1241–6.CrossRefPubMedGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  1. 1.Wayne State University School of MedicineDetroitUSA

Personalised recommendations