Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 5, Pages 3049-3056Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.5.3049
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Funding
- Pennsylvania Department of Health
- Tobacco Formula Funding
- National Institutes of Health [AA10384, AA016688]
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA010384, R29AA010384, R01AA016688] Funding Source: NIH RePORTER
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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-kappa B 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.
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