Molecular Medicine

, Volume 13, Issue 7–8, pp 362–370 | Cite as

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

  • Hajo Haase
  • Dawn J. Mazzatti
  • Andrew White
  • Klaus H. Ibs
  • Gabriela Engelhardt
  • Silke Hebel
  • Jonathan R. Powell
  • Lothar Rink


An individual’s zinc status has a significant impact on the immune system, and zinc deficiency, as well as supplementation, modulates immune function. To investigate the effects of zinc on different leukocyte subsets, we used microarray technology to analyze and compare the changes in mRNA expression in cell culture models of monocytes (THP-1), T cells (Jurkat), and B cells (Raji), in response to supplementation for 40 h with 50 µM zinc or 2.5 µM of the membrane-permeant zinc chelator TPEN [N,N,N′,N′- tetrakis-(2-pyridyl-methyl)ethylenediamine], respectively. In each cell type, several hundred genes were identified to be zinc sensitive, but only a total of seven genes were commonly regulated in all three cell lines. The majority of those genes were involved in zinc homeostasis, and none in immune function. Nevertheless, further analysis revealed that zinc affects entire functional networks of genes that are related to proinflammatory cytokines and cellular survival. Although the zinc-regulated activities are similar throughout the gene networks, the specific genes that are affected vary significantly between different cell types, a situation that helps to elucidate the disparity of the effects that zinc has on different leukocyte populations.



We thank Ann Scarborough for technical assistance with the microarrays. This study was partially supported by DFG grant HA4318/3-2 and the EU project ZINCAGE (Food-CT-2003-506850).


  1. 1.
    Beyersmann D, Haase H. (2001) Function of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14:331–41.CrossRefGoogle Scholar
  2. 2.
    Cousins RJ, Blanchard RK, Popp MP, Liu L, Cao J, Moore JB, Green CL. (2003) A global view of the selectivity of zinc deprivation and excess on genes expressed in human THP-1 mononuclear cells. Proc. Natl. Acad. Sci. U S A 100:6952–7.CrossRefGoogle Scholar
  3. 3.
    Daniel H, tom Dieck H. (2004) Nutrient-gene interactions: a single nutrient and hundreds of target genes. Biol. Chem. 385:571–83.CrossRefGoogle Scholar
  4. 4.
    Beck FW, Li Y, Bao B, Prasad AS, Sarkar FH. (2006) Evidence for reprogramming global gene expression during zinc deficiency in the HUT-78 cell line. Nutrition 22:1045–56.CrossRefGoogle Scholar
  5. 5.
    Wellinghausen N, Kirchner H, Rink L. (1997) The immunobiology of zinc. Immunol. Today 18: 519–21.CrossRefGoogle Scholar
  6. 6.
    Zoli A, Altomonte L, Caricchio R, Galossi A, Mirone L, Ruffini MP, Magaro M. (1998) Serum zinc and copper in active rheumatoid arthritis: correlation with interleukin 1 beta and tumor necrosis factor alpha. Clin. Rheumatol. 17:378–82.CrossRefGoogle Scholar
  7. 7.
    Chausmer AB. (1998) Zinc, insulin and diabetes. J. Am. Coll. Nutr. 17:109–15.CrossRefGoogle Scholar
  8. 8.
    Truong-Tran AQ, Carter J, Ruffin R, Zalewski PD. (2001) New insights into the role of zinc in the respiratory epithelium. Immunol. Cell Biol. 79: 170–7.CrossRefGoogle Scholar
  9. 9.
    Schott-Ohly P, Lgssiar A, Partke HJ, Hassan M, Friesen N, Gleichmann H. (2004) Prevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-kappa B and AP-1 in islets, respectively. Exp. Biol. Med. (Maywood) 229:1177–85.CrossRefGoogle Scholar
  10. 10.
    Simkin PA. (1976) Oral zinc sulphate in rheumatoid arthritis. Lancet 2:539–42.CrossRefGoogle Scholar
  11. 11.
    Haase H, Mocchegiani E, Rink L. (2006) Correlation between zinc status and immune function in the elderly. Biogerontology 7:421–8.CrossRefGoogle Scholar
  12. 12.
    von Bülow V, Rink L, Haase H. (2005) Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-alpha and IL-1 beta production in monocytes by elevation of guanosine 3′,5′-cyclic monophosphate. J. Immunol. 175:4697–4705.CrossRefGoogle Scholar
  13. 13.
    Snyder SL, Walker RI. (1976) Inhibition of lethality in endotoxin-challenged mice treated with zinc chloride. Infect. Immun. 13:998–1000.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Krones C, Klosterhalfen B, Fackeldey V, et al. (2004) Deleterious effect of zinc in a pig model of acute endotoxemia. J. Invest. Surg. 17:249–56.CrossRefGoogle Scholar
  15. 15.
    Jarrard DF. (2005) Does zinc supplementation increase the risk of prostate cancer? Arch. Ophthalmol. 123:102–3.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Haase H, Hebel S, Engelhardt G, Rink L. (2006) Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal. Biochem. 352:222–30.CrossRefGoogle Scholar
  18. 18.
    Grynkiewicz G, Poenie M, Tsien RY. (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260:3440–50.PubMedGoogle Scholar
  19. 19.
    Faneyte IF, Kristel PM, van de Vijver MJ. (2001) Determining MDR1/P-glycoprotein expression in breast cancer. Int. J. Cancer 93: 114–22.CrossRefGoogle Scholar
  20. 20.
    tom Dieck H, Doring F, Fuchs D, Roth HP, Daniel H. (2005) Transcriptome and proteome analysis identifies the pathways that increase hepatic lipid accumulation in zinc-deficient rats. J. Nutr. 135:199–205.CrossRefGoogle Scholar
  21. 21.
    tom Dieck H, Doring F, Roth HP, Daniel H. (2003) Changes in rat hepatic gene expression in response to zinc deficiency as assessed by DNA arrays. J. Nutr. 133:1004–10.CrossRefGoogle Scholar
  22. 22.
    Aydemir TB, Blanchard RK, Cousins RJ. (2006) Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations. Proc. Natl. Acad. Sci. U S A 103:1699–1704.CrossRefGoogle Scholar
  23. 23.
    Andree KB, Kim J, Kirschke CP, et al. (2004) Investigation of lymphocyte gene expression for use as biomarkers for zinc status in humans. J. Nutr. 134:1716–23.CrossRefGoogle Scholar
  24. 24.
    Andrews GK. (2001) Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 14:223–37.CrossRefGoogle Scholar
  25. 25.
    Friesema EC, Jansen J, Visser TJ. (2005) Thyroid hormone transporters. Biochem. Soc. Trans. 33: 228–32.CrossRefGoogle Scholar
  26. 26.
    Ballatori N, Hammond CL, Cunningham JB, Krance SM, Marchan R. (2005) Molecular mechanisms of reduced glutathione transport: role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicol. Appl. Pharmacol. 204:238–55.CrossRefGoogle Scholar
  27. 27.
    Maret W. (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid. Redox Signal. 8:1419–41.CrossRefGoogle Scholar
  28. 28.
    Notkins AL, Lan MS, Leslie RD. (1998) IA-2 and IA-2beta: the immune response in IDDM. Diabetes Metab. Rev. 14:85–93.CrossRefGoogle Scholar
  29. 29.
    Arslan P, Di Virgilio F, Beltrame M, Tsien RY, Pozzan T. (1985) Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas: a new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J. Biol. Chem. 260:2719–27.PubMedGoogle Scholar
  30. 30.
    Maret W, Jacob C, Vallee BL, Fischer EH. (1999) Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc. Natl. Acad. Sci. U S A 96:1936–40.CrossRefGoogle Scholar
  31. 31.
    Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD. (2001) The role of zinc in caspase activation and apoptotic cell death. Biometals 14:315–30.CrossRefGoogle Scholar
  32. 32.
    Fraker PJ. (2005) Roles for cell death in zinc deficiency. J. Nutr. 135:359–62.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Hajo Haase
    • 1
  • Dawn J. Mazzatti
    • 2
  • Andrew White
    • 3
  • Klaus H. Ibs
    • 1
  • Gabriela Engelhardt
    • 1
  • Silke Hebel
    • 1
  • Jonathan R. Powell
    • 2
  • Lothar Rink
    • 1
  1. 1.Institute of Immunology, University HospitalRWTH Aachen UniversityAachenGermany
  2. 2.Unilever Corporate ResearchSharnbrookUK
  3. 3.Unilever Measurement SciencesSharnbrookUK

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