Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells

Metallomics. 2012 Oct;4(10):1088-97. doi: 10.1039/c2mt20118f. Epub 2012 Sep 14.


Mild zinc deficiency in humans negatively affects IL-2 production resulting in declined percentages of cytolytic T cells and decreased NK cell lytic activity, which enhances the susceptibility to infections and malignancies. T-cell activation is critically regulated by zinc and the normal physiological zinc level in T-cells slightly lies below the optimal concentration for T-cell functions. A further reduction in zinc level leads to T-cell dysfunction and autoreactivity, whereas high zinc concentrations (100 μM) were shown to inhibit interleukin-1 (IL-1)-induced IL-1 receptor kinase (IRAK) activation. In this study, we investigated the molecular mechanism by which zinc regulates the IL-1β-induced IL-2 expression in T-cells. Zinc supplementation to zinc-deficient T-cells increased intracellular zinc levels by altering the expression of zinc transporters, particularly Zip10 and Zip12. A zinc signal was observed in the murine T-cell line EL-4 6.1 after 1 h of stimulation with IL-1β, measured by specific zinc sensors FluoZin-3 and ZinPyr-1. This signal is required for the phosphorylation of MAPK p38 and NF-κB subunit p65, which triggers the transcription of IL-2 and strongly increases its production. These results indicate that short-term zinc supplementation to zinc-deficient T-cells leads to a fast rise in zinc levels which subsequently enhance cytokine production. In conclusion, low and excessive zinc levels might be equally problematic for zinc-deficient subjects, and stabilized zinc levels seem to be essential to avoid negative concentration-dependent zinc effects on T-cell activation.

MeSH terms

  • Animals
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Gene Expression Regulation / drug effects*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Interleukin-2 / biosynthesis*
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Mice
  • Phosphorylation
  • Signal Transduction
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Up-Regulation / drug effects
  • Zinc / deficiency
  • Zinc / metabolism
  • Zinc / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Cation Transport Proteins
  • Interleukin-1beta
  • Interleukin-2
  • Transcription Factor RelA
  • p38 Mitogen-Activated Protein Kinases
  • Zinc