Nuclear factor of activated T cells (NFAT) as a molecular target for 1α,25-dihydroxyvitamin D3-mediated effects

Atsuko Takeuchi, G. Satyanarayana Reddy, Tadashi Kobayashi, Toshio Okano, Jungchan Park, Surendra Sharma

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular basis of the immunomodulatory properties of 1α,25- dihydroxyvitamin D3 (1α, 25(OH)2D3) remains elusive. We demonstrate here that 1α,25(OH)2D3-mediated suppressive effects on the inducible expression of cytokine genes in human T Cells may, in part, be due to diminished activity of the transcription factor NFAT. The vitamin D3 receptor (VDR) and its heterodimeric partner retinoid X receptor α (RXRα) specifically bound to the distal NFAT site in the human IL-2 promoter, and this binding was abolished by mutating unique regions in the NFAT oligonucleotide. In vitro inhibition of NFAT complex formation was noted when VDR-RXRα heterodimers were added to DNA binding reactions containing nuclear extracts from activated B or T cells, whereas in vitro NFκB complex formation was not significantly influenced. Furthermore, 1α,25(OH)2D3 treatment of activated T cells resulted in decreased formation of NFAT complexes detected upon incubation of nuclear extracts from these cells with 32P-labeled probe. Transient expression of both VDR and RXRα, but not of a single component, was capable of inhibiting expression of a NFAT-driven reporter gene in stimulated Jurkat cells in a ligand-dependent manner. These results suggest that NFAT plays a crucial role in 1α,25(OH)2D3-mediated immunosuppressive activity.

Original languageEnglish (US)
Pages (from-to)209-218
Number of pages10
JournalJournal of Immunology
Volume160
Issue number1
StatePublished - Jan 1 1998
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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