CYCLOSPORINE-A INTERFERES WITH THE INDUCIBLE DEGRADATION OF NF-KAPPA-B INHIBITORS, BUT NOT WITH THE PROCESSING OF P105 NF-KAPPA-B1 IN T-CELLS/

The transcription factor NF-kappa B controls the induction of numerous cytokine promoters during the activation of T lymphocytes. Inhibition of T cell activation by the immunosuppressants cyclosporin A (CsA) an d FK506 exerts a suppressive effect on the induction of these NF-kappa B-controlled cytokine promoters. We show for human Jurkat T leukemia cells, as well as human and mouse primary T lymphocytes, that this inh ibitory effect is accompanied by an impaired nuclear translocation of the Rel proteins c-Rel, Re1A/p65 and NF-kappa B1/p50, whereas the nucl ear appearance of RelB remains unaffected. CsA does not interfere with the synthesis of Rel proteins, but prevents the inducible degradation of cytosolic NF-kappa B inhibitors I kappa B alpha and I kappa B beta upon T cell activation. CsA neither inhibits the processing of the NF -kappa B1 precursor p105 to p50, nor does it ''stabilize'' the C-termi nal portion of p105, I kappa B gamma, which is degraded during p105 pr ocessing to mature p50. These results indicate that CsA interferes wit h a specific event in the signal-induced degradation of I kappa B alph a and I kappa B beta, but does not affect the processing of NF-kappa B 1/p105 to p50.