Nature 357, 692 - 694 (25 June 1992); doi:10.1038/357692a0

FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin

Stephen J. O'Keefe^*, Jun'ichi Tamura^†‡, Randall L. Kincaid^†, Michael J. Tocci^* & Edward A. O'Neill^*

^* Department of Molecular Immunology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
^† Section on Immunology, Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852, USA
^‡Present address: Third Department of Internal Medicine, Gunma University Medical School, Maebashi, Gunma 371, Japan.

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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