FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin

Nature. 1992 Jun 25;357(6380):692-4. doi: 10.1038/357692a0.


Antigen recognition by the T-cell receptor (TCR) initiates events including lymphokine gene transcription, particularly interleukin-2, that lead to T-cell activation. The immunosuppressive drugs, cyclosporin A (CsA) and FK-506, prevent T-cell proliferation by inhibiting a Ca(2+)-dependent event required for induction of interleukin-2 transcription. Complexes of FK-506 or CsA and their respective intracellular binding proteins inhibit the calmodulin-dependent protein phosphatase, calcineurin, in vitro. The pharmacological relevance of this observation to immunosuppression or drug toxicity is undetermined. Calcineurin, although present in lymphocytes, has not been implicated in TCR-mediated activation of lymphokine genes or in transcriptional regulation in general. Here we report that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner. These results implicate calcineurin as a component of the TCR signal transduction pathway by demonstrating its role in the drug-sensitive activation of the interleukin-2 promoter.

MeSH terms

  • Animals
  • Calcineurin
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism*
  • Cell Line
  • Chloramphenicol O-Acetyltransferase / genetics
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Chromosome Deletion
  • Cyclosporine / pharmacology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Interleukin-2 / genetics*
  • Ionomycin / pharmacology
  • Kinetics
  • Macromolecular Substances
  • Mice
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic / drug effects*
  • Recombinant Proteins / metabolism
  • Tacrolimus / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription, Genetic / drug effects
  • Transfection


  • Calmodulin-Binding Proteins
  • Interleukin-2
  • Macromolecular Substances
  • Recombinant Proteins
  • Ionomycin
  • Cyclosporine
  • Chloramphenicol O-Acetyltransferase
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Tetradecanoylphorbol Acetate
  • Tacrolimus