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

Eur J Immunol. 1998 Oct;28(10):3017-30. doi: 10.1002/(SICI)1521-4141(199810)28:10<3017::AID-IMMU3017>3.0.CO;2-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Calcitriol / metabolism*
  • Enhancer Elements, Genetic
  • Gene Expression Regulation*
  • Humans
  • Interferon-gamma / genetics*
  • Jurkat Cells
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoid X Receptors
  • Sequence Deletion
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • Receptors, Calcitriol
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors
  • Interferon-gamma
  • Calcitriol