FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin.
Antigen recognition by the T-cell receptor (TCR) initiates events including lymphokine gene transcription, particularly interleukin-2, that lead to T-cell activation. The immunosuppressive drugs, cyclosporin A (CsA) and FK-506, prevent T-cell proliferation by inhibiting a Ca(2+)-dependent event required for induction of interleukin-2 transcription. Complexes of FK-506 or CsA and their respective intracellular binding proteins inhibit the calmodulin-dependent protein phosphatase, calcineurin, in vitro. The pharmacological relevance of this observation to immunosuppression or drug toxicity is undetermined. Calcineurin, although present in lymphocytes, has not been implicated in TCR-mediated activation of lymphokine genes or in transcriptional regulation in general. Here we report that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner. These results implicate calcineurin as a component of the TCR signal transduction pathway by demonstrating its role in the drug-sensitive activation of the interleukin-2 promoter.
O'Keefe
S J
SJ
Department of Molecular Immunology, Merck Research Laboratories, Rahway, New Jersey 07065.
Tamura
J
J
Kincaid
R L
RL
Tocci
M J
MJ
O'Neill
E A
EA
D000818:Animals; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002872:Chromosome Deletion; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D002148:Calmodulin-Binding Proteins; D007376:Interleukin-2; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D015759:Ionomycin; D016572:Cyclosporine; D015500:Chloramphenicol O-Acetyltransferase; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus