TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol

J Immunol. 2008 Sep 1;181(5):3049-56. doi: 10.4049/jimmunol.181.5.3049.


Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF-alpha production by macrophages and Kupffer cells and signaling via the p55 TNF receptor have been shown to be critical for these effects of chronic EtOH; however, the molecular mechanisms leading to augmented TNF-alpha production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF-alpha transcription, which is independent of NF-kappaB. Using reporter assays and chromatin immunoprecipitation we found that this increased transcription is due to increased IRF-3 binding to and transactivation of the TNF promoter. As IRF-3 is downstream from the TLR4 adaptor TIR-domain-containing adapter-inducing IFN-beta (Trif), we demonstrate that macrophages from Trif-/- mice are resistant to this dysregulation of TNF-alpha transcription by EtOH in vitro as well as EtOH-induced steatosis and TNF dysregulation in vivo. These data demonstrate that the Trif/IRF-3 pathway is a target to ameliorate liver dysfunction associated with chronic EtOH.

Publication types

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

MeSH terms

  • Adaptor Proteins, Vesicular Transport / deficiency
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Adaptor Proteins, Vesicular Transport / physiology*
  • Alcoholism / complications
  • Animals
  • Bone Marrow
  • Cells, Cultured
  • Ethanol / toxicity*
  • Fatty Liver / chemically induced*
  • Fatty Liver / etiology
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-3 / physiology*
  • Macrophages
  • Male
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic*
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / genetics*


  • Adaptor Proteins, Vesicular Transport
  • Interferon Regulatory Factor-3
  • TICAM-1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Ethanol