Vitamin D3: a transcriptional modulator of the interferon‐γ gene

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.