Molecular mode of action of cyclosporin and FK506 in human thymocytes.
The molecular mode of action of cyclosporin, three of its non-immunosuppressive analogs, N-methyl-l-alanyl cyclosporin, acetyl cyclosporin and cyclosporin S3, and of FK506 was studied in primary cultures of human thymocytes. Nuclear factors derived from thymocytes activated with phorbol myristate acetate and concanavalin A were tested for their ability to bind to a synthetic radiolabelled probe corresponding to the NF-AT region (-285 to -255) of the IL-2 gene. Binding was observed, and it was inhibited by CsA (100 ng/ml), while the analogs at ten-fold higher concentrations (1000 ng/ml) were only partially inhibitory. CsA in combination with FK506 inhibited binding of nuclear factors at the NF-AT site, and acted in concert.
Reem
G H
GH
Department of Pharmacology, New York University Medical Center, New York 10016.
D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D007376:Interleukin-2 / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000187:drug effects / Q000502:physiology; D015345:Oligonucleotide Probes; D016559:Tacrolimus / Q000494:pharmacology*; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D003524:Cyclosporins; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D009687:Nuclear Proteins; D015345:Oligonucleotide Probes; D016572:Cyclosporine; D016559:Tacrolimus