Early growth response-1 attenuates liver injury and promotes hepatoprotection after carbon tetrachloride exposure in mice

JOURNAL OF HEPATOLOGY

卷:53

Article

Pritchard, Michele T.¹  Cohen, Jessica I.^1,3  Roychowdhury, Sanjoy¹  Pratt, Brian T.¹  Nagy, Laura E.^1,2,3 

[1] Cleveland Clin, Dept Pathobiol, Cleveland, OH 44195 USA

[2] Cleveland Clin, Dept Gastroenterol, Cleveland, OH 44195 USA

[3] Case Western Reserve Univ, Dept Nutr, Cleveland, OH 44106 USA

关键词: Early growth response-1;    Inflammation;    Hepatoprotection;    Carbon tetrachloride;   

DOI  :  10.1016/j.jhep.2010.04.017

来源: Elsevier

【 摘 要 】

Background & Aims: Inflammatory gene expression plays a pathological role in acute and chronic hepatic inflammation, yet, inflammation also promotes liver repair by inducing protective mechanisms to limit collateral tissue damage by priming hepatocytes for proliferation. Early growth response (Egr)-1, a transcription factor that regulates inflammatory gene expression, plays a pathological role in many animal models of acute and chronic inflammatory disease. Here, we tested the hypothesis that Egr-1 is beneficial after toxic liver injury. Methods: Acute liver injury was induced in wild-type and egr-1-/- mice by a single injection of carbon tetrachloride (CCl4). Liver injury, inflammatory, and hepatoprotective gene expression and signaling events were measured 18, 48, and 72 h after CCl4 administration. Results: Peak liver injury was greater in egr-1-/- mice compared to wild-type mice. Enhanced injury in egr-1-/- mice was associated with reduced tumor necrosis factor (TNF)alpha mRNA and protein expression, reduced Akt phosphorylation and nuclear localization of NF kappa B-p65 in nuclei of cells in the hepatic sinusoid. Expression of inducible nitric oxide synthase and cyclooxygenase-2, TNF alpha-regulated genes that have hepatoprotective function, was attenuated in egr-1-/- mice compared to wild-type mice. Although plasma interleukin (IL)-6 protein and hepatic accumulation of IL-6, glycoprotein 130, and IL-6 receptor a mRNA in wild-type and egr-1-/- mice were equivalent, signal transducer and activator of transcription 3 phosphorylation was attenuated in egr-1-/- mice and associated with reduced oncostatin M expression. Conclusions: In contrast to its role in inflammation-mediated tissue injury in other models, Egr-1 expression promotes protection in the liver after CCl4 exposure. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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