Skip to main content

Advertisement

SpringerLink
Log in

Signal transduction in monocytes: the role of zinc ions

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The availability of zinc has a regulatory role in the immune system. It can have either pro- or anti-inflammatory effects, which both seem to be a consequence of a direct interaction of zinc with the cytokine secretion by monocytes. In this review, the molecular basis for this effect, the interaction of zinc with the signal transduction of monocytes, is discussed. In particular, zinc seems to activate or inhibit several signaling pathways that interact with the signal transduction of pathogen sensing receptors, the so-called Toll-like receptors (TLR), which sense pathogen-derived molecular structures and, upon activation, lead to secretion of pro-inflammatory cytokines. The interaction of zinc with protein tyrosine phosphatases and protein kinase C, and a direct modulation of lipopolysaccharide binding to its receptor (TLR-4) all result in enhanced cytokine production. On the other hand, a complex interaction between zinc, NO and cyclic nucleotide signaling, and inhibition of interleukin-1 receptor associated kinase-1, and inhibitor of kappa B kinase all counteract the production of pro-inflammatory cytokines. A role for the zinc binding protein metallothionein as a regulator for intracellular zinc signaling is discussed. By acting on all these signaling molecules, the zinc status of monocytes can have a direct effect on inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Andrews GK (2001) Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 14:223–237

    Article  CAS  PubMed  Google Scholar 

  • Arbibe L, Mira JP, Teusch N et al (2000) Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol 1:533–540

    Article  CAS  PubMed  Google Scholar 

  • Bao B, Prasad AS, Beck FW, Godmere M (2003) Zinc modulates mRNA levels of cytokines. Am J Physiol 285:E1095–E1102

    CAS  Google Scholar 

  • Beyersmann D, Haase H (2001) Function of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 14:331–341

    Article  CAS  PubMed  Google Scholar 

  • Brautigan DL, Bornstein P, Gallis B (1981) Phosphotyrosyl-protein phosphatase. Specific inhibition by Zn. J Biol Chem 256:6519–6522

    CAS  PubMed  Google Scholar 

  • Cousins RJ, Blanchard RK, Popp MP et al (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 USA 100:6952–6957

    Article  CAS  PubMed  Google Scholar 

  • De SK, McMaster MT, Andrews GK (1990) Endotoxin induction of murine metallothionein gene expression. J Biol Chem 65:15267–15274

    Google Scholar 

  • Donnelly TE (1978) Effects of zinc chloride on the hydrolysis of cyclic GMP and cyclic AMP by the activator-dependent cyclic nucleotide phosphodiesterase from bovine heart. Biochim Biophys Acta 522:151–160

    CAS  PubMed  Google Scholar 

  • Driessen C, Hirv K, Kirchner H, Rink L (1995a) Divergent effects of zinc on different bacterial pathogenic agents. J Infect Dis 171:486–489

    CAS  PubMed  Google Scholar 

  • Driessen C, Hirv K, Kirchner H, Rink L (1995b) Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology 84:272–277

    CAS  PubMed  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 Cytokine Res 13:15–20

    CAS  PubMed  Google Scholar 

  • Francis SH, Colbran JL, McAllister-Lucas LM, Corbin JD (1994) Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J Biol Chem 269:22477–22480

    CAS  PubMed  Google Scholar 

  • Gao X, Du Z, Patel TB (2005) Copper and zinc inhibit Galphas function: a nucleotide-free state of Galphas induced by Cu2+ and Zn2+. J Biol Chem 280:2579–2586

    Article  CAS  PubMed  Google Scholar 

  • Geng Y, Zhang B, Lotz M (1993) Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol 151:6692–6700

    CAS  PubMed  Google Scholar 

  • Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O’Neill LA (2006) MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J Biol Chem 281:10489–10495

    Article  CAS  PubMed  Google Scholar 

  • Haase H, Hebel S, Engelhardt G, Rink L (2006) Flow cytometric measurement of labile zinc in peripheral blood mononuclear cells. Anal Biochem 352:222–230

    Article  CAS  PubMed  Google Scholar 

  • Haase H, Maret W (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291:289–298

    Article  CAS  PubMed  Google Scholar 

  • Jefferies CA, Doyle S, Brunner C et al (2003) Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 278:26258–26264

    Article  CAS  PubMed  Google Scholar 

  • Jeon KI, Jeong JY, Jue DM (2000) Thiol-reactive metal compounds inhibit NF-kappa B activation by blocking I kappa B kinase. J Immunol 164:5981–5989

    CAS  PubMed  Google Scholar 

  • Kim YM, Reed W, Wu W, Bromberg PA, Graves LM, Samet JM (2006) Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells. Am J Physiol 290:L1028–L1035

    CAS  Google Scholar 

  • Klein C, Heyduk T, Sunahara RK (2004) Zinc inhibition of adenylyl cyclase correlates with conformational changes in the enzyme. Cell Signal 16:1177–1185

    Article  CAS  PubMed  Google Scholar 

  • Klein C, Sunahara RK, Hudson TY, Heyduk T, Howlett AC (2002) Zinc inhibition of cAMP signaling. J Biol Chem 277:11859–11865

    Article  CAS  PubMed  Google Scholar 

  • Krones CJ, Klosterhalfen B, Butz N et al (2005) Effect of zinc pretreatment on pulmonary endothelial cells in vitro and pulmonary function in a porcine model of endotoxemia. J Surg Res 123:251–256

    Article  CAS  PubMed  Google Scholar 

  • Krones C, Klosterhalfen B, Fackeldey V et al (2004) Deleterious effect of zinc in a pig model of acute endotoxemia. J Invest Surg 17:249–256

    Article  PubMed  Google Scholar 

  • Leibbrandt ME, Koropatnick J (1994) Activation of human monocytes with lipopolysaccharide induces metallothionein expression and is diminished by zinc. Toxicol Appl Pharmacol 124:72–81

    Article  CAS  PubMed  Google Scholar 

  • Leibbrandt ME, Khokha R, Koropatnick J (1994) Antisense down-regulation of metallothionein in a human monocytic cell line alters adherence, invasion, and the respiratory burst. Cell Growth Differ 5:17–25

    CAS  PubMed  Google Scholar 

  • Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal (in press)

  • Maret W, Jacob C, Vallee BL, Fischer EH (1999) Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc Natl Acad Sci USA 96:1936–1940

    Article  CAS  PubMed  Google Scholar 

  • Martin MU, Wesche H (2002) Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochim Biophys Acta 1592:265–280

    Article  CAS  PubMed  Google Scholar 

  • Munro AW, Taylor P, Walkinshaw MD (2000) Structures of redox enzymes. Curr Opin Biotechnol 11:369–376

    Article  CAS  PubMed  Google Scholar 

  • Omburo GA, Jacobitz S, Torphy TJ, Colman RW (1998) Critical role of conserved histidine pairs HNXXH and HDXXH in recombinant human phosphodiesterase 4A. Cell Signal 10:491–497

    Article  CAS  PubMed  Google Scholar 

  • Percival MD, Yeh B, Falgueyret JP (1997) Zinc dependent activation of cAMP-specific phosphodiesterase (PDE4A). Biochem Biophys Res Commun 241:175–180

    Article  CAS  PubMed  Google Scholar 

  • Rink L, Gabriel P (2001) Extracellular and immunological actions of zinc. Biometals 14:367–383

    Article  CAS  PubMed  Google Scholar 

  • Snyder SL, Walker RI (1976) Inhibition of lethality in endotoxin-challenged mice treated with zinc chloride. Infect Immun 13:998–1000

    CAS  PubMed  Google Scholar 

  • Sugiura T, Kuroda E, Yamashita U (2004) Dysfunction of macrophages in metallothionein-knock out mice. J UOEH 26:193–205

    CAS  PubMed  Google Scholar 

  • Tan SL, Parker PJ (2003) Emerging and diverse roles of protein kinase C in immune cell signalling. Biochem J 376:545–552

    Article  CAS  PubMed  Google Scholar 

  • von Bülow V, Rink L, Haase H (2005) Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-α and IL-1β production in monocytes by elevation of cGMP. J Immunol 175:4697–4705

    Google Scholar 

  • Wätjen W, Benters J, Haase H, Schwede F, Jastorff B, Beyersmann D (2001) Zn2+ and Cd2+ increase the cyclic GMP level in PC12 cells by inhibition of the cyclic nucleotide phosphodiesterase. Toxicology 157:167–175

    Article  PubMed  Google Scholar 

  • Wellinghausen N, Driessen C, Rink L (1996a) Stimulation of human peripheral blood mononuclear cells by zinc and related cations. Cytokine 8:767–771

    Article  CAS  PubMed  Google Scholar 

  • Wellinghausen N, Fischer A, Kirchner H, Rink L (1996b) Interaction of zinc ions with human peripheral blood mononuclear cells. Cell Immunol 171:255–261

    CAS  PubMed  Google Scholar 

  • Wellinghausen N, Schromm AB, Seydel U et al (1996c) Zinc enhances lipopolysaccharide-induced monokine secretion by alteration of fluidity state of lipopolysaccharide. J Immunol 157:3139–3145

    CAS  PubMed  Google Scholar 

  • Wellinghausen N., Kirchner H., Rink L. (1997a) The immunobiology of zinc. Immunol Today 18:519–521

    Article  CAS  PubMed  Google Scholar 

  • Wellinghausen N, Martin M, Rink L (1997b) Zinc inhibits IL-1 dependent T cell stimulation. Eur J Immunol 27:2529–2535

    Article  CAS  PubMed  Google Scholar 

  • Youn J, Borghesi LA, Olson EA, Lynes MA (1995) Immunomodulatory activities of extracellular metallothionein. II. Effects on macrophage functions. J Toxicol Environ Health 45:397–413

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany

    Hajo Haase & Lothar Rink

Authors
  1. Hajo Haase
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lothar Rink
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hajo Haase.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haase, H., Rink, L. Signal transduction in monocytes: the role of zinc ions. Biometals 20, 579–585 (2007). https://doi.org/10.1007/s10534-006-9029-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-006-9029-8

Keywords

Search

Navigation