Cyclosporin A interferes with the inducible degradation of NF‐xB inhibitors, but not with the processing of p105/NF‐xB1 in T cells

Abstract

The transcription factor NF‐xB controls the induction of numerous cytokine promoters during the activation of T lymphocytes. Inhibition of T cell activation by the immunosuppressants cyclosporin A (CsA) and FK506 exerts a suppressive effect on the induction of these NF‐xB‐controlled cytokine promoters. We show for human Jurkat T leukemia cells, as well as human and mouse primary T lymphocytes, that this inhibitory effect is accompanied by an impaired nuclear translocation of the Rel proteins c‐Rel, RelA/p65 and NF‐xB1/p50, whereas the nuclear appearance of RelB remains unaffected. CsA does not interfere with the synthesis of Rel proteins, but prevents the inducible degradation of cytosolic NF‐xB inhibitors IxBα and IxBβ upon T cell activation. CsA neither inhibits the processing of the NF‐xB1 precursor p105 to p50, nor does it “stabilize” the C‐terminal portion of p105, IxBγ, which is degraded during p105 processing to mature p50. These results indicate that CsA interferes with a specific event in the signal‐induced degradation of IxBα and IxBβ, but does not affect the processing of NF‐xB1/p105 to p50.