Activation of nuclear factor of activated T cells in a cyclosporin A- resistant pathway

P. Ghosh, A. Sica, M. Cippitelli, J. Subleski, R. Lahesmaa, H. A. Young, N. R. Rice

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism of action of the immunosuppressive drug cyclosporin A (CsA) is the inactivation of the Ca 2+/calmodulin-dependent serine-threonine phosphatase calcineurin by the drug-immunophilin complex. Inactive calcineurin is unable to activate the nuclear factor of activated T cells (NFAT), a transcription factor required for expression of the interleukin 2 (IL-2) gene. IL-2 production by CsA-treated cells is therefore dramatically reduced. We demonstrate here, however, that NFAT can be activated, and significant levels of IL-2 can be produced by the CsA-resistant CD28- signaling pathway. In transient transfection assays, both multicopy NFAT- and IL-2 promoter-β-galactosidase reporter gene constructs could be activated by phorbol 12-myristate 13-acetate (PMA)/αCD28 stimulation, and this activation was resistant to CsA. Electrophoretic mobility shift assay showed the induction of a CsA-resistant NFAT complex in the nuclear extracts of peripheral blood T cells stimulated with PMA plus αCD28. Peripheral blood T cells stimulated with PMA/αCD28 produced IL-2 in the presence of CsA. Collectively, these data suggest that NFAT can be activated and IL-2 can be produced in a calcineurin independent manner.

Original languageEnglish
Pages (from-to)7700-7704
Number of pages5
JournalJournal of Biological Chemistry
Volume271
Issue number13
DOIs
Publication statusPublished - 1996

ASJC Scopus subject areas

  • Biochemistry

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