TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes

Nat Immunol. 2008 Apr;9(4):378-87. doi: 10.1038/ni1576. Epub 2008 Mar 16.


Rapid induction of inflammatory genes by tumor necrosis factor (TNF) has been well studied, but little is known about delayed and chronic TNF responses. Here we investigated the kinetics of primary macrophage responses to TNF and discovered that TNF initiates an interferon-beta-mediated autocrine loop that sustains expression of inflammatory genes and induces delayed expression of interferon-response genes such as those encoding the transcription factors STAT1 and IRF7, which enhance macrophage responses to stimulation of cytokines and Toll-like receptors. TNF-induced interferon-beta production depended on interferon-response factor 1, and downstream gene expression was mediated by synergy between small amounts of interferon-beta and canonical TNF-induced signals. Thus, TNF activates a 'feed-forward' loop that sustains inflammation but avoids the potential toxicity associated with the high interferon production induced by stimulation of Toll-like receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autocrine Communication / immunology*
  • Chemokines / biosynthesis*
  • Chemokines / genetics*
  • Gene Expression Regulation / immunology*
  • Humans
  • Inflammation Mediators / physiology
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferon Regulatory Factor-1 / physiology
  • Interferon Type I / biosynthesis
  • Interferon Type I / genetics*
  • Interferon Type I / physiology
  • Interferon-beta / biosynthesis
  • Interferon-beta / genetics
  • Interferon-beta / physiology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • STAT1 Transcription Factor / physiology*
  • Time Factors
  • Tumor Necrosis Factor-alpha / physiology*


  • Chemokines
  • IRF1 protein, human
  • Inflammation Mediators
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Tumor Necrosis Factor-alpha
  • Interferon-beta