Original article

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

  • Meike KrügerAffiliated withDepartment of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • , M. SchwaningerAffiliated withDepartment of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • , Roland BlumeAffiliated withDepartment of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • , Elke OetjenAffiliated withDepartment of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany
  • , W. KnepelAffiliated withDepartment of Molecular Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany

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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