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TRIF and IRF-3 Binding to the TNF Promoter Results in Macrophage TNF Dysregulation and Steatosis Induced by Chronic Ethanol¹

Xue-Jun Zhao^*, Qing Dong^*, Julie Bindas^*, Jon D. Piganelli, Amy Magill^*, Jakob Reiser and Jay K. Kolls^2,*

^* Department of Pediatrics and Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213; and Department of Medicine Gene Therapy Program, Louisiana State University School of Medicine, New Orleans, LA 70112

Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF- 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- production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF- transcription, which is independent of NF-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-β (Trif), we demonstrate that macrophages from Trif–/– mice are resistant to this dysregulation of TNF- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported, in part, by the Pennsylvania Department of Health, Tobacco Formula Funding and by National Institutes of Health Grants AA10384 and AA016688 (to J.K.K.).

² Address correspondence and reprint requests to Dr. Jay K. Kolls, Children’s Hospital of Pittsburgh, Suite 3765, 3705 Fifth Avenue, Pittsburgh, PA 15213.

³ Abbreviations used in this paper: EtOH, ethanol; WT, wild type; Trif, TIR-domain-containing adapter-inducing IFN-β; ISRE, IFN-stimulated response element; IP, immunoprecipitation; BM, bone marrow; ChIP, Chromatin IP; ALT, alanine aminotransferase; IBSR, IB super repressor.

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