Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 356, Issue 4, pp 433–440

Inhibition of CREB- and cAMP response element-mediated gene transcription by the immunosuppressive drugs cyclosporin A and FK506 in T cells

Authors

  • Meike Krüger
    • Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • M. Schwaninger
    • Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • Roland Blume
    • Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • Elke Oetjen
    • Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • W. Knepel
    • Department of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
Original article

DOI: 10.1007/PL00005073

Cite this article as:
Krüger, M., Schwaninger, M., Blume, R. et al. Naunyn-Schmiedeberg's Arch Pharmacol (1997) 356: 433. doi:10.1007/PL00005073

Abstract

The clinically important immunosuppressant drugs cyclosporin A and FK506 (tacrolimus) inhibit in T-cells calcineurin phosphatase activity and nuclear translocation of the cytosolic component of the transcription factor nuclear factor of activated T-cells (NF-ATc) that is involved in the induction of early genes during T-cell activation. This effect has been proposed to explain at least part of the immunosuppressive effect of these drugs. Previous studies in pancreatic islet cell lines have shown that cyclosporin A and FK506 through inhibition of calcineurin interfere also with the function of the transcription factor cAMP response element binding protein (CREB) that is activated by cAMP and calcium signals and binds to cAMP/calcium response elements (CRE). By transient expression of CRE-reporter genes or GAL4-CREB fusion proteins, the present study shows that inhibition of CREB/ CRE-directed transcription by cyclosporin A and FK506 occurs in a great variety of cell types including in cell lines derived from tissues in which adverse effects of the immunosuppressants develop. CREB activity and CRE-mediated transcription was blocked by these drugs also in Jurkat T-cells. When taken together with recent evidence for an essential role of CREB in T-cell activation and proliferation, the present results suggest that inhibition of CREB/CRE-directed transcription may be a molecular mechanism of the immunosuppressive effect of cyclosporin A and FK506.

Key words Cyclosporin A FK506 cAMP response element CREB Transcription Immunosuppressive drugs T-cells

Copyright information

© Springer-Verlag Berlin Heidelberg 1997