INHIBITION OF CREB-RESPONSE AND CAMP-RESPONSE ELEMENT-MEDIATED GENE-TRANSCRIPTION BY THE IMMUNOSUPPRESSIVE DRUGS CYCLOSPORINE-A AND FK506 IN T-CELLS

The clinically important immunosuppressant drugs cyclosporin A and FK5 06 (tacrolimus) inhibit in T-cells calcineurin phosphatase activity an d nuclear translocation of the cytosolic component of the transcriptio n 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 e ffect of these drugs. Previous studies in pancreatic islet cell lines have shown that cyclosporin A and FK506 through inhibition of calcineu rin 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 GALA-CREB fusion protein s, the present study shows that inhibition of CREB/CRE-directed transc ription by cyclosporin A and FK506 occurs in a great variety of cell t ypes including in cell lines derived from tissues in which adverse eff ects 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 st molecular mech anism of the immunosuppressive effect of cyclosporin A and FK506.