Divergent effects of dithiocarbamates on AP-1-containing and AP-1-less NFAT sites

Eur J Immunol. 1999 Apr;29(4):1194-201. doi: 10.1002/(SICI)1521-4141(199904)29:04<1194::AID-IMMU1194>3.0.CO;2-0.


Changes in the redox status of cells affect NF-kappaB and activator protein (AP)-1 nuclear expression and activity. In particular, antioxidants decrease NF-kappaB and increase AP-1 transcriptional activity, thereby regulating gene expression. In T cells, low concentrations of antioxidants enhance IL-2 and inhibit IL-4 expression. Since NFAT binding sites play an essential role in regulating IL-2 and IL-4 gene transcription, we studied the effects of dithiocarbamates, using the pyrrolidine derivative of dithiocarbamate (PDTC), on the activity of the distinct AP-1-containing IL-2 NFAT and AP-1-less IL-4 NFAT enhancers elements. Consistent with the presence of AP-1 proteins within the IL-2 NFAT complex, PDTC strongly enhanced phorbol 12-myristate 13-acetate/phytohemagglutinin-induced NFAT binding to the IL-2 NFAT enhancer and transcriptional activity of a reporter plasmid driven by this NFAT enhancer. In contrast, the activity of the IL-4 NFp enhancer, which does not bind AP-1, was abolished by PDTC treatment. In the Jurkat T cell line treated with PDTC, co-expression of the Ca2+/calmodulin-dependent phosphatase, calcineurin, completely restored the IL-4 NFp enhancer activity. Our data indicate that calcineurin-mediated NFAT activity is a target for antioxidants and provides new insights into the molecular mechanisms controlling differential cytokine gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology*
  • Calcineurin / pharmacology
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic
  • Humans
  • Interleukin-2 / metabolism
  • Interleukin-4 / metabolism
  • Jurkat Cells
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Pyrrolidines / pharmacology*
  • Thiocarbamates / pharmacology*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects


  • Antioxidants
  • DNA-Binding Proteins
  • Interleukin-2
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Pyrrolidines
  • Thiocarbamates
  • Transcription Factor AP-1
  • Transcription Factors
  • Interleukin-4
  • DNA
  • Calcineurin
  • pyrrolidine