Cyclosporin A and FK506 prevent the derepression of the IL-2 gene in mitogen-induced primary T lymphocytes.
In resting primary T lymphocytes the interleukin 2 (IL-2) gene is silenced by a repressor binding to the Pud element spanning positions -292 to -264 upstream of the cap site. Upon T-cell activation, this silencer is displaced by a positive transcription factor (TF) and the gene is derepressed and transcribed. Cyclosporin A (CsA) and FK506 interfere with normal derepression of the IL-2 gene. Both drugs exert no direct effect on basal transcription of the IL-2 or control viral genes. Direct addition does not abolish the active state of positive TFs present in proteins from activated T cells. However, if T cells are activated in the presence of either drug, their proteins not only fail to derepress, but efficiently and irreversibly silence IL-2 transcription. DNA-protein binding data show that proteins present in drug-treated cells form retarded complexes corresponding in size to the silencer and positive TF. Thus, in drug-treated cells a functional silencer persists, and a positive TF-like factor appears which is functionally abnormal. Moreover, drug-treated T cells appear to form a component that prevents functioning of normal positive TF.
Mouzaki
A
A
Geneva University Hospital, Switzerland.
Dai
Y
Y
Weil
R
R
Rungger
D
D
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008934:Mitogens; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D014981:Xenopus
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008934:Mitogens; D012097:Repressor Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D016559:Tacrolimus