Early growth response-1 attenuates liver injury and promotes hepatoprotection after carbon tetrachloride exposure in mice.
OBJECTIVE
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 (CCl(4)). Liver injury, inflammatory, and hepatoprotective gene expression and signaling events were measured 18, 48, and 72 h after CCl(4) 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 NFkappaB-p65 in nuclei of cells in the hepatic sinusoid. Expression of inducible nitric oxide synthase and cyclooxygenase-2, TNFalpha-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 alpha 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 CCl(4) exposure.
Pritchard
Michele T
MT
Department of Pathobiology, Cleveland Clinic, Cleveland, OH 44195, USA. pritchm@ccf.org
Cohen
Jessica I
JI
Roychowdhury
Sanjoy
S
Pratt
Brian T
BT
Nagy
Laura E
LE
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
D051766:Early Growth Response Protein 1; D002251:Carbon Tetrachloride