| First Author | Zhao XJ | Year | 2008 |
| Journal | J Immunol | Volume | 181 |
| Issue | 5 | Pages | 3049-56 |
| PubMed ID | 18713975 | Mgi Jnum | J:138963 |
| Mgi Id | MGI:3806913 | Doi | 10.4049/jimmunol.181.5.3049 |
| Citation | Zhao XJ, et al. (2008) TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J Immunol 181(5):3049-56 |
| abstractText | 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. |
