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,25-Dihydroxyvitamin D3-Mediated Effects
*
Section of Experimental Pathology, Department of Pathology, Roger Williams Medical Center, Brown University, Providence, RI 02908;
Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI 02903; and
Department of Hygienic Sciences, Kobe Pharmaceutical University, Kobe, Japan
The molecular basis of the immunomodulatory properties of
1
,25-dihydroxyvitamin D3
(1,25(OH)2D3) remains elusive. We
demonstrate here that 1,25(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 (RXR)
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-RXR heterodimers were added to DNA binding reactions
containing nuclear extracts from activated B or T cells, whereas in
vitro NF
B complex formation was not significantly influenced.
Furthermore, 1,25(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
RXR, 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 1,25(OH)2D3-mediated
immunosuppressive activity.
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