FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin (original) (raw)

Nature volume 357, pages 692–694 (1992)Cite this article

Abstract

ANTIGEN recognition by the T-cell receptor (TCR) initiates events including lymphokine gene transcription1, 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 Ca2+-dependent event required for induction of interleukin-2 transcription2. Complexes of FK-506 or CsA and their respective intracellular binding proteins inhibit the calmodulin-dependent protein phosphatase, calcineurin, _in vitro_3. The pharmacological relevance of this observation to immunosuppression or drug toxicity is undetermined. Calcineurin, although present in lymphocytes4, 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.

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Author notes

  1. Jun'ichi Tamura
    Present address: Third Department of Internal Medicine, Gunma University Medical School, Maebashi, Gunma, 371, Japan

Authors and Affiliations

  1. Department of Molecular Immunology, Merck Research Laboratories, Rahway, New Jersey, 07065, USA
    Stephen J. O'Keefe, Michael J. Tocci & Edward A. O'Neill
  2. Section on Immunology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, 20852, USA
    Jun'ichi Tamura & Randall L. Kincaid

Authors

  1. Stephen J. O'Keefe
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  2. Jun'ichi Tamura
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  3. Randall L. Kincaid
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  4. Michael J. Tocci
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  5. Edward A. O'Neill
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O'Keefe, S., Tamura, J., Kincaid, R. et al. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin.Nature 357, 692–694 (1992). https://doi.org/10.1038/357692a0

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