The effect of immunosuppressive agents on the induction of nuclear factors that bind to sites on the interleukin 2 promoter.
Cyclosporin A (CSA), FK506, and glucocorticosteroids all inhibit the production of lymphokines by decreasing lymphokine gene expression. Previous experiments have defined six different sites that may contribute to the transcriptional control of the interleukin 2 (IL-2) promoter, and for each, active nuclear binding factors are induced upon mitogenic stimulation. While dexamethasone markedly blocks the increase in IL-2 mRNA in stimulated human blood T cells, we found that the drug does not block the appearance of factors that bind to the transcriptional control sites termed AP-1, AP-3, NF-kB, OCT-1, B site, and NF-AT. In contrast, both CSA and FK506 have similar effects: the drugs cause modest decreases in AP-3 and NF-kB, and markedly decreases in the activity of AP-1 and NF-AT. Therefore, CSA and FK506, while chemically different, seem to act upon a similar pathway that leads to IL-2 gene expression, whereas glucocorticoids do not affect this pathway.
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, New York 10021.
A
A
Granelli-Piperno
P
P
Nolan
K
K
Inaba
R M
RM
Steinman
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001483:Base Sequence; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016559:Tacrolimus; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D003524:Cyclosporins; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015345:Oligonucleotide Probes; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus