RANK signaling induces interferon-stimulated genes in the fetal thymic stroma

Biochem Biophys Res Commun. 2011 May 20;408(4):530-6. doi: 10.1016/j.bbrc.2011.04.049. Epub 2011 Apr 19.

Abstract

Medullary thymic epithelial cells (mTECs) are essential for thymic negative selection to prevent autoimmunity. Previous studies show that mTEC development is dependent on the signal transducers TRAF6 and NIK. However, the downstream target genes of signals controlled by these molecules remain unknown. We performed a microarray analysis on mRNAs down-regulated by deficiencies in TRAF6 or functional NIK in an in vitro organ culture of fetal thymic stromata (2DG-FTOC). An in silico analysis of transcription factor binding sites in plausible promoter regions of differentially expressed genes suggests that STAT1 is involved in TRAF6- and NIK-dependent gene expression. Indeed, the signal of RANK, a TNF receptor family member that activates TRAF6 and NIK, induces the activation of STAT1 in 2DG-FTOC. Moreover, RANK signaling induces the up-regulation of interferon (IFN)-stimulated gene (ISG) expression, suggesting that the RANKL-dependent activation of STAT1 up-regulates ISG expression. The RANKL-dependent expression levels of ISGs were reduced but not completely abolished in interferon α receptor 1-deficient (Ifnar1(-/-)) 2DG-FTOC. Our data suggest that RANK signaling induces ISG expression in both type I interferon-independent and interferon-dependent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Cells / immunology*
  • Fetus
  • Gene Expression Regulation*
  • Interferon Type I / immunology*
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Receptor, Interferon alpha-beta / genetics
  • Self Tolerance / genetics*
  • Signal Transduction
  • Stromal Cells / immunology
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • Thymus Gland / immunology*

Substances

  • Interferon Type I
  • Receptor Activator of Nuclear Factor-kappa B
  • TNF Receptor-Associated Factor 6
  • Tnfrsf11a protein, mouse
  • Receptor, Interferon alpha-beta
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase