Vitamin D3: a transcriptional modulator of the interferon-gamma gene.
1Alpha,25-dihydroxyvitamin D3 [1,25-(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-gamma in T cells. Here, we analyze the effect of 1,25-(OH)2D3 on IFN-gamma gene transcription. Transient transfection assays in Jurkat T cells indicate that activation of the IFN-gamma 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-gamma 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-gamma minimal promoter, suggesting a possible mechanism of interference with transcription initiation/progression. The overall data indicate that direct modulation of the IFN-gamma promoter activity is one of the possible mechanisms involved in the repressive effect of 1,25-(OH)2D3 on IFN-gamma gene expression.
Cippitelli
M
M
Laboratory of Pathophysiology, Regina Elena Cancer Institute, Rome, Italy. cippitelli@ifo.it
Santoni
A
A
D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D007371:Interferon-gamma; D002117:Calcitriol