1α,25-Dihydroxyvitamin D3 [1225-(OH)2D3] exerts several effects on the immune system, by regulating lymphocyte proliferation, differentiation of monocytes and secretion of cytokines as IL-2, granulocyte-macrophage colony-stimulating factor and IFN-γ in T cells. Here, we analyze the effect of 1,25-(OH)2D3 on IFN-γ gene transcription. Transient transfection assays in Jurkat T cells indicate that activation of the IFN-γ promoter is down-regulated by 1,25-(OH)2D3. This effect is enhanced by retinoid X receptor (RXR), and a functional vitamin D3 receptor (VDR) DNA-binding domain in necessary for repression. We delineated two important promoter regions mainly involved in this modulation. The first of these is situated at the level of a promoter-silencer previously characterized and binds the heterodimer VDR-RXR in electrophoretic mobility shift assay. Residual negative regulation was also detected at the level of the promoter fragment -108 to +64 bp from the transcription start site and, surprisingly, the activity of the IFN-γ enhancer from -108 to -36 bp in the context of a heterologous promoter was not affected by 1,25-(OH)2D3. Moreover, binding activity for VDR-RXR has been detected in the IFN-γ minimal promoter, suggesting a possible mechanism of interference with transcription initiation/progression. The overall data indicate that direct modulation of the IFN-γ promoter activity is one of the possible mechanisms involved in the repressive effect of 1,25-(OH)2D3 on IFN-γ gene expression.
|Number of pages||14|
|Journal||European Journal of Immunology|
|Publication status||Published - Oct 1998|
- Gene transcription
- Nuclear receptor
- Vitamin D receptor
ASJC Scopus subject areas