Twist mediates suppression of inflammation by type I IFNs and Axl

J Exp Med. 2006 Aug 7;203(8):1891-901. doi: 10.1084/jem.20051725. Epub 2006 Jul 10.

Abstract

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFalpha production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFalpha production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFalpha production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-kappaB-dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFalpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Cells, Cultured
  • Cytokines / genetics
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation / immunology*
  • Interferon-alpha / pharmacology*
  • Macrophages / drug effects
  • Mice
  • Models, Biological
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Fc / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Twist-Related Protein 1 / metabolism*

Substances

  • Cytokines
  • Interferon-alpha
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Fc
  • TLR2 protein, human
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Twist-Related Protein 1
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase