Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription

Mol Cell Biol. 2002 Apr;22(8):2777-87. doi: 10.1128/MCB.22.8.2777-2787.2002.

Abstract

The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Calcitriol / administration & dosage
  • Calcitriol / metabolism*
  • Calcitriol / pharmacology*
  • Cell Line
  • Chemokine CXCL10
  • Chemokines, CXC / biosynthesis
  • Cytochrome P-450 Enzyme System / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Synergism
  • Humans
  • Interferon-gamma / administration & dosage
  • Interferon-gamma / pharmacology
  • Macromolecular Substances
  • Models, Biological
  • Receptors, Calcitriol / metabolism*
  • Receptors, Retinoic Acid / metabolism
  • Recombinant Proteins
  • Retinoid X Receptors
  • STAT1 Transcription Factor
  • Signal Transduction
  • Steroid Hydroxylases / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Vitamin D3 24-Hydroxylase

Substances

  • Chemokine CXCL10
  • Chemokines, CXC
  • DNA-Binding Proteins
  • Macromolecular Substances
  • Receptors, Calcitriol
  • Receptors, Retinoic Acid
  • Recombinant Proteins
  • Retinoid X Receptors
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Transcription Factors
  • Interferon-gamma
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • Calcitriol