tacrolimus and Chromosome-Deletion

Topics: Amino Acid Isomerases; Animals; Carrier Proteins; Chromosome Deletion; Cyclosporine; Humans; Immunosuppressive Agents; Neurospora crassa; Peptidylprolyl Isomerase; Saccharomyces cerevisiae; Tacrolimus; Tacrolimus Binding Proteins

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.

Topics: Animals; Calcineurin; Calmodulin-Binding Proteins; Cell Line; Chloramphenicol O-Acetyltransferase; Chromosome Deletion; Cyclosporine; Gene Expression Regulation; Humans; Interleukin-2; Ionomycin; Kinetics; Macromolecular Substances; Mice; Phosphoprotein Phosphatases; Polymerase Chain Reaction; Promoter Regions, Genetic; Recombinant Proteins; Tacrolimus; Tetradecanoylphorbol Acetate; Transcription, Genetic; Transfection