Cyclosporin A suppresses the expression of the interleukin 2 gene by inhibiting the binding of lymphocyte-specific factors to the IL-2 enhancer.
Cyclosporin A (CsA), a powerful immunosuppressive drug, inhibits the synthesis of lymphokines in T lymphocytes at the level of gene transcription. Using protein extracts from El4 lymphoma cells we show that the binding of lymphocyte-specific factors interacting with the two so-called purine boxes (Pu-boxes) of the interleukin 2 (IL-2) enhancer are missing in CsA-treated cells. The CsA-sensitive factors are newly synthesized upon induction. The most prominent factor consists of 45 kd polypeptides and contacts both Pu-boxes at the two central G residues within the identical core sequence AAGAGGAAAA. The CsA-mediated suppression of factor binding to the Pu-boxes correlates well with functional studies in which the inducible, T cell-restricted proto-enhancer activity of Pu-boxes was selectively repressed by CsA. These observations support the conclusion that the suppression of factor binding to the Pu-boxes by CsA impairs the activity of IL-2 and of further lymphokine genes, thereby inhibiting the synthesis of lymphokines in T lymphocytes.
Randak
C
C
Institut für Virologie und Immunbiologie, Universität Würzburg, FRG.
Brabletz
T
T
Hergenröther
M
M
Sobotta
I
I
Serfling
E
E
D000818:Animals; D001483:Base Sequence; D003208:Concanavalin A / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012689:Sequence Homology, Nucleic Acid; D013489:Suppression, Genetic / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects
D003524:Cyclosporins; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008222:Lymphokines; D003208:Concanavalin A; D003609:Dactinomycin; D003513:Cycloheximide