Rapamycin potentiates dexamethasone-induced apoptosis and inhibits JNK activity in lymphoblastoid cells.
The immunosuppressant rapamycin (RAP) potentiated apoptosis of the murine T lymphoblastoid cell line S49 induced by dexamethasone (DEX), while RAP by itself did not induce apoptosis of the cells. FK506, in contrast, had no effect on DEX-induced apoptosis; moreover, an excess of FK506 reversed the potentiation of apoptosis by RAP, indicating that RAP exerts its effects through binding to FKBP. Both RAP and FK506 enhanced the MMTV promoter activity by dexamethasone, suggesting that the potentiation of apoptosis is not likely explained by the selective enhancement of transcriptional activity of the glucocorticoid receptor. Of interest, the basal activity of c-Jun kinase (JNK), whose activation has been recently suggested to be involved in cell survival signals in lymphocytes, was reduced by RAP in S49 cells. The reduction of JNK activity by RAP was reversed by the addition of an excess of FK506. In summary, we demonstrate for the first time that RAP has the ability to inhibit JNK activity in lymphocytes where the drug enhances apoptosis.
Ishizuka
T
T
Division of Basic Sciences, Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Sakata
N
N
Johnson
G L
GL
Gelfand
E W
EW
Terada
N
N
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D011090:Polyenes / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D020123:Sirolimus; D013601:T-Lymphocytes; D016559:Tacrolimus / Q000494:pharmacology; D014162:Transfection
D007166:Immunosuppressive Agents; D011090:Polyenes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D003907:Dexamethasone; D008156:Luciferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus; D016559:Tacrolimus