Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation.
One action of cyclosporin A thought to be central to many of its immunosuppressive effects is its ability to inhibit the early events of T lymphocyte activation such as lymphokine gene transcription in response to signals initiated at the antigen receptor. Cyclosporin A was found to specifically inhibit the appearance of DNA binding activity of NF-AT, AP-3, and to a lesser extent NF-kappa B, nuclear proteins that appear to be important in the transcriptional activation of the genes for interleukin-2 and its receptor, as well as several other lymphokines. In addition, cyclosporin A abolished the ability of the NF-AT binding site to activate a linked promoter in transfected mitogen-stimulated T lymphocytes and in lymphocytes from transgenic mice. These results indicate that cyclosporin A either directly inhibits the function of nuclear proteins critical to T lymphocyte activation or inhibits the action of a more proximal member of the signal transmission cascade leading from the antigen receptor to the nucleus.
Emmel
E A
EA
Howard Hughes Medical Institute, Stanford University, CA 94305.
Verweij
C L
CL
Durand
D B
DB
Higgins
K M
KM
Lacy
E
E
Crabtree
G R
GR
D001483:Base Sequence; D002460:Cell Line; D002872:Chromosome Deletion; D003524:Cyclosporins / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D015345:Oligonucleotide Probes; D015375:Receptors, Interleukin-2 / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic
D003524:Cyclosporins; D007376:Interleukin-2; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D015375:Receptors, Interleukin-2