title: TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol.
abstract: 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.
authors: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Xue-Jun
authors: XJ
authors: Zhao
authors: Qing
authors: Q
authors: Dong
authors: Julie
authors: J
authors: Bindas
authors: Jon D
authors: JD
authors: Piganelli
authors: Amy
authors: A
authors: Magill
authors: Jakob
authors: J
authors: Reiser
authors: Jay K
authors: JK
authors: Kolls
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000437:Alcoholism / Q000150:complications; D000818:Animals; D001853:Bone Marrow; D002478:Cells, Cultured; D000431:Ethanol / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000209:etiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000431:Ethanol; D050838:Interferon Regulatory Factor-3; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse