Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function


Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Decrease in intracellular free zinc in DCs after LPS treatment.
Figure 2: Intracellular zinc depletion mimics and zinc supplementation blocks LPS-induced DC maturation.
Figure 3: Intracellular trafficking and endocytosis of MHC class II are blocked by TPEN treatment.
Figure 4: LPS-induced alterations in zinc transporter expression depend on TRIF.
Figure 5: Zip6 overexpression blocks LPS-induced reduction in intracellular free zinc and upregulation of surface MHC class II.
Figure 6: LPS treatment reduces intracellular free zinc and alters expression of zinc transporters in splenic CD11c+ cells in vivo.

Similar content being viewed by others


  1. Prasad, A.S. Zinc: an overview. Nutrition 11, 93–99 (1995).

    CAS  PubMed  Google Scholar 

  2. Vallee, B.L. & Falchuk, K.H. The biochemical basis of zinc physiology. Physiol. Rev. 73, 79–118 (1993).

    Article  CAS  Google Scholar 

  3. Pabo, C.O., Peisach, E. & Grant, R.A. Design and selection of novel Cys2His2 zinc finger proteins. Annu. Rev. Biochem. 70, 313–340 (2001).

    Article  CAS  Google Scholar 

  4. Joazeiro, C.A. & Weissman, A.M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).

    Article  CAS  Google Scholar 

  5. Kadrmas, J.L. & Beckerle, M.C. The LIM domain: from the cytoskeleton to the nucleus. Nat. Rev. Mol. Cell Biol. 5, 920–931 (2004).

    Article  CAS  Google Scholar 

  6. Vallee, B.L. The function of metallothionein. Neurochem. Int. 27, 23–33 (1995).

    Article  CAS  Google Scholar 

  7. Eide, D.J. The SLC39 family of metal ion transporters. Pflugers Arch. 447, 796–800 (2004).

    Article  CAS  Google Scholar 

  8. Palmiter, R.D. & Huang, L. Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch. 447, 744–751 (2004).

    Article  CAS  Google Scholar 

  9. Colvin, R.A., Fontaine, C.P., Laskowski, M. & Thomas, D. Zn2+ transporters and Zn2+ homeostasis in neurons. Eur. J. Pharmacol. 479, 171–185 (2003).

    Article  CAS  Google Scholar 

  10. Kambe, T., Yamaguchi-Iwai, Y., Sasaki, R. & Nagao, M. Overview of mammalian zinc transporters. Cell. Mol. Life Sci. 61, 49–68 (2004).

    Article  CAS  Google Scholar 

  11. Yamashita, S. et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature 429, 298–302 (2004).

    Article  CAS  Google Scholar 

  12. Siklar, Z., Tuna, C., Dallar, Y. & Tanyer, G. Zinc deficiency: a contributing factor of short stature in growth hormone deficient children. J. Trop. Pediatr. 49, 187–188 (2003).

    Article  Google Scholar 

  13. Ganss, B. & Jheon, A. Zinc finger transcription factors in skeletal development. Crit. Rev. Oral Biol. Med. 15, 282–297 (2004).

    Article  Google Scholar 

  14. Ashworth, A., Morris, S.S., Lira, P.I. & Grantham-McGregor, S.M. Zinc supplementation, mental development and behaviour in low birth weight term infants in northeast Brazil. Eur. J. Clin. Nutr. 52, 223–227 (1998).

    Article  CAS  Google Scholar 

  15. Licastro, F. et al. Immune-endocrine status and coeliac disease in children with Down's syndrome: relationships with zinc and cognitive efficiency. Brain Res. Bull. 55, 313–317 (2001).

    Article  CAS  Google Scholar 

  16. Prasad, A.S. Zinc and immunity. Mol. Cell. Biochem. 188, 63–69 (1998).

    Article  CAS  Google Scholar 

  17. Fraker, P.J. & King, L.E. Reprogramming of the immune system during zinc deficiency. Annu. Rev. Nutr. 24, 277–298 (2004).

    Article  CAS  Google Scholar 

  18. Fisher, W.C. & Black, R.E. Zinc and the risk for infectious disease. Annu. Rev. Nutr. 24, 255–275 (2004).

    Article  Google Scholar 

  19. Hosea, H.J., Rector, E.S. & Taylor, C.G. Zinc-deficient rats have fewer recent thymic emigrant (CD90+) T lymphocytes in spleen and blood. J. Nutr. 133, 4239–4242 (2003).

    Article  CAS  Google Scholar 

  20. Prasad, A.S. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J. Infect. Dis. 182, S62–S68 (2000).

    Article  CAS  Google Scholar 

  21. Ibs, K.H. & Rink, L. Zinc-altered immune function. J. Nutr. 133, 1452S–1456S (2003).

    Article  CAS  Google Scholar 

  22. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  Google Scholar 

  23. Mellman, I. & Steinman, R.M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001).

    Article  CAS  Google Scholar 

  24. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    Article  CAS  Google Scholar 

  25. Pierre, P. et al. Developmental regulation of MHC class II transport in mouse dendritic cells. Nature 388, 787–792 (1997).

    Article  CAS  Google Scholar 

  26. Turley, S.J. et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288, 522–527 (2000).

    Article  CAS  Google Scholar 

  27. Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002).

    Article  CAS  Google Scholar 

  28. Trombetta, E.S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005).

    Article  CAS  Google Scholar 

  29. Villadangos, J.A. et al. MHC class II expression is regulated in dendritic cells independently of invariant chain degradation. Immunity 14, 739–749 (2001).

    Article  CAS  Google Scholar 

  30. Tamura, T. et al. The role of antigenic peptide in CD4+ T helper phenotype development in a T cell receptor transgenic model. Int. Immunol. 16, 1691–1699 (2004).

    Article  CAS  Google Scholar 

  31. Prasad, A.S. Zinc: an overview. Nutrition 11, 93–99 (1995).

    CAS  PubMed  Google Scholar 

  32. Palmiter, R.D. & Huang, L. Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch. 447, 744–751 (2004).

    Article  CAS  Google Scholar 

  33. Liuzzi, J.P. & Cousins, R.J. Mammalian zinc transporters. Annu. Rev. Nutr. 24, 151–172 (2004).

    Article  CAS  Google Scholar 

  34. Takeda, K. & Akira, S. TLR signaling pathways. Semin. Immunol. 16, 3–9 (2004).

    Article  CAS  Google Scholar 

  35. Palmiter, R.D. Protection against zinc toxicity by metallothionein and zinc transporter 1. Proc. Natl. Acad. Sci. USA 101, 4918–4923 (2004).

    Article  CAS  Google Scholar 

  36. Aballay, A., Stahl, P.D. & Mayorga, L.S. Phorbol ester promotes endocytosis by activating a factor involved in endosome fusion. J. Cell Sci. 112, 2549–2557 (1999).

    CAS  PubMed  Google Scholar 

  37. Garrett, W.S.C.L., Kroschewski, R., Ebersold, M., Turley, S., Trombetta, S., Galan, J.E. & Mellman, I. Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102, 325–334 (2000).

    Article  CAS  Google Scholar 

  38. Aballay, A., Stahl, P.D. & Mayorga, L.S. Phorbol ester promotes endocytosis by activating a factor involved in endosome fusion. J. Cell Sci. 112, 2549–2557 (1999).

    CAS  PubMed  Google Scholar 

  39. Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688–5694 (2001).

    Article  CAS  Google Scholar 

  40. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).

    Article  CAS  Google Scholar 

  41. Park, S.J. et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173, 3844–3854 (2004).

    Article  CAS  Google Scholar 

  42. Kitamura, H. et al. IL-6-STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in dendritic cells. Immunity 23, 491–502 (2005).

    Article  CAS  Google Scholar 

Download references


We thank K. Takatsu (University of Tokyo, Tokyo, Japan) for P25 TCR–transgenic mice; T. Saito (RIKEN RCAI, Yokohama, Japan) for Phoenix cells; T. Sudo (Toray, Kamakura, Japan) for CHO cells producing granulocyte-macrophage colony-stimulating factor; T. Mitchell (University of Louisville, Louisville, Kentucky) for the pMSCV-IRES-Thy1.1 retroviral vector; O. Ohara (DNA Kazusa, Kazusa and RIKEN RCAI, Yokohama, Japan) for mouse Zip6 cDNA; A. Ito, T. Yamasaki, E. Iketani and T. Hayashi for technical assistance; and R. Masuda and M. Shimura for secretarial assistance. Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (S.Y., M.M. and T.H.), the Uehara Foundation (M.M.) and the Osaka Foundation for the Promotion of Clinical Immunology (M.M. and T.H.).

Author information

Authors and Affiliations



H.K. and H.M. did most of the experiments; H.K. helped with retrovirus infection and did experiments using T cells; M.I. helped with the quantitative PCR; S.H. helped with the flow cytometry; T.F. and S.Y. provided advice for the experiments and manuscript; T.K. and S.A. provided knockout mice and some reagents and advice for the experiments and manuscript; and M.M. and T.H. designed all the experiments and prepared the manuscript.

Corresponding author

Correspondence to Toshio Hirano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

TPEN increased surface expression of MHCII and MHCI but not that of CD40 and CD80 molecules in DCs. (PDF 69 kb)

Supplementary Fig. 2

TPEN treatment, which decreased intracellular zinc did not alter expression of H2-Ab1 or Cd86 mRNA and did not induce cytokine expression in DCs. (PDF 83 kb)

Supplementary Fig. 3

Effect of TPEN on DC maturation was not due to contaminating endotoxin. (PDF 100 kb)

Supplementary Fig. 4

Zinc ion plus zinc pyrithione but not zinc ion or zinc pyrithione alone inhibited LPS-induced decrease of free zinc in DCs. (PDF 86 kb)

Supplementary Fig. 5

LPS and polyIC but not R-848 and CpG treatment decreased intracellular zinc level in DCs. (PDF 48 kb)

Supplementary Fig. 6

TPEN injection increased surface expression of MHCII molecules on DCs. (PDF 27 kb)

Supplementary Fig. 7

Zinc plus pyrithione treatment inhibited R-848- and CpG-induced upregulation of MHCII and CD86 in DCs. (PDF 30 kb)

Supplementary Fig. 8

Specificity of anti-Zip6 polyclonal antibody. (PDF 245 kb)

Supplementary Table 1

PCR primers. (PDF 17 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kitamura, H., Morikawa, H., Kamon, H. et al. Toll-like receptor–mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol 7, 971–977 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing