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

Abstract

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.