Research Article| Volume 53, ISSUE 4, P655-662, October 2010

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

      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.


      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.


      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)α mRNA and protein expression, reduced Akt phosphorylation and nuclear localization of NFκB-p65 in nuclei of cells in the hepatic sinusoid. Expression of inducible nitric oxide synthase and cyclooxygenase-2, TNFα-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 α 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.


      In contrast to its role in inflammation-mediated tissue injury in other models, Egr-1 expression promotes protection in the liver after CCl4 exposure.


      LPS (lipopolysaccharide), TNFα (tumor necrosis factor α), IL-6 (interleukin 6), CCl4 (carbon tetrachloride), Egr-1 (early growth response-1), CYP2E1 (cytochrome P450 2E1), NFκB-p65 (nuclear factor κB p65 subunit), ROS (reactive oxygen species), h (hours), ALT (alanine aminotransferase), AST (aspartate aminotransferase), TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), Ct (threshold cycle), ELISA (enzyme-linked immunosorbent assay), SEM (standard error of the mean), STAT 3 (signal transducer and activator of transcription 3), iNOS (inducible form of nitric oxide synthase), COX-2 (cyclooxygenase-2), gp130 (glycoprotein 130kDa), OSM (oncostatin M), OSMR (oncostatin M receptor), TNFR1 (tumor necrosis factor receptor 1), NO (nitric oxide)


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