Cyclosporin 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) and 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 inhibitory effect is accompanied by an impaired nuclear translocation of the Rel proteins c-Rel, RelA/p65 and NF-kappa B1/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-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-terminal portion of p105, I kappa B gamma, 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 I kappa B alpha and I kappa B beta, but does not affect the processing of NF-kappa B1/p105 to p50.
Marienfeld
R
R
Department of Molecular Pathology, University of Würzburg, Germany.
Neumann
M
M
Chuvpilo
S
S
Escher
C
C
Kneitz
B
B
Avots
A
A
Schimpl
A
A
Serfling
E
E
D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors
D009097:Multienzyme Complexes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB; D016572:Cyclosporine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D016559:Tacrolimus