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)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.
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.
Abbreviations:
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)Keywords
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References
- Inhibition of cyclooxygenase-2 aggravates secretory phospholipase A2-mediated progression of acute liver injury.Toxicol Appl Pharmacol. 2008; 228: 239-246
- Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2.Toxicol Appl Pharmacol. 2008; 228: 225-238
- Hepatocyte-specific inhibition of NF-κB leads to apoptosis after TNF treatment, but not after partial hepatectomy.J Clin Invest. 2002; 110: 193-202
- Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide.Br J Pharmacol. 1997; 121: 820-826
- Liver regeneration.Hepatology. 2006; 43 (2): S45-S53
- Rapid DNA binding by nuclear factor kappa B in hepatocytes at the start of liver regeneration.Cell Growth Differ. 1995; 6: 417-427
- Therapeutic potential of interleukin-6 in preventing obesity- and alcohol-associated fatty liver transplant failure.Alcohol (Fayetteville, NY). 2004; 34: 59-65
- Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors.Prog Nucleic Acid Res Mol Biol. 1995; 50: 191-224
- Oncostatin M: signal transduction and biological activity.Life Sci. 1999; 65: 2019-2030
- Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats.Am J Pathol. 2007; 171: 872-881
- Principles of interleukin (IL)-6-type cytokine signalling and its regulation.Biochem J. 2003; 374: 1-20
- Stimulation of hepatocyte survival and suppression of CCl4-induced liver injury by the adenovirally introduced C/EBPbeta gene.Biochem Biophys Res Commun. 2005; 329: 182-187
- Protection of hepatotoxic and lethal effects of CCl4 by partial hepatectomy.Toxicol Pathol. 1989; 17: 494-505
- Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1).Science. 1996; 273: 1219-1221
- Cloning and characterization of human oncostatin M promoter.Nucleic acids Res. 1999; 27: 4649-4657
- Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.Environ Health Perspect. 1996; 104: 744-749
- Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice.Gastroenterology. 2005; 128: 2066-2076
- Tissue repair: an important determinant of final outcome of toxicant-induced injury.Toxicol Pathol. 2005; 33: 41-51
- Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice.Toxicol Appl Pharmacol. 2001; 172: 44-51
- Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice.Hepatology. 2004; 39: 635-644
- Ethanol-induced liver injury: potential roles for egr-1.Alcohol Clin Exp Res. 2005; 29: 146S-150S
- Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice.Am J Physiol Gastrointest Liver Physiol. 2007; 293: G1124-G1133
- Liver cytoprotection by prostaglandins.Pharmacol Ther. 1993; 58: 67-91
- Impaired liver regeneration in inducible nitric oxide synthase deficient mice.Proc Natl Acad Sci USA. 1998; 95: 13829-13834
- Regulation of inducible nitric oxide synthase messenger RNA expression and nitric oxide production by lipopolysaccharide in vivo: the roles of macrophages, endogenous IFN-gamma, and TNF receptor-1-mediated signaling.J Immunol. 1997; 158: 905-912
- Cyclooxygenases: structural, cellular, and molecular biology.Annu Rev Biochem. 2000; 69: 145-182
- Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases.Hepatology. 2003; 38: 218-229
- Liver regeneration: from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847
- Transcriptional regulatory signals define cytokine-dependent and -independent pathways in liver regeneration.Semin Liver Dis. 1999; 19: 117-127
- Inducible nitric oxide synthase in the liver: regulation and function.Biochemistry (Mosc). 1998; 63: 766-781
- Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection.J Gastroenterol Hepatol. 2003; 18: 891-902
- Involvement of TNF and NF-kappa B in the transcriptional control of cyclooxygenase-2 expression by IFN-gamma in macrophages.J Immunol. 2005; 174: 2825-2833
- Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.Crit Rev Toxicol. 2003; 33: 105-136
- Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors.J Biol Chem. 1997; 272: 17795-17801
- Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice.J Hepatol. 2004; 40: 926-933
Article info
Publication history
Published online: June 18, 2010
Accepted:
April 26,
2010
Received in revised form:
April 23,
2010
Received:
October 5,
2009
Identification
Copyright
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
