Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice.
Early growth response (Egr)-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation, and wound healing; however, little is known about the role of Egr-1 in acute liver injury. We tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure biphasically increased hepatic egr-1 mRNA accumulation at 1 h and again at 4-5.5 h after treatment in wild-type mice. Within 4-5.5 h after GalN/LPS exposure, wild-type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma alanine aminotransferase activities. In contrast, these parameters were largely attenuated in egr-1(-/-) mice. The initial expression of tumor necrosis factor-alpha, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 mRNA or protein was equivalent between genotypes at 1 h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1(-/-) compared with wild-type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1(-/-) compared with wild-type mice 4 h after GalN/LPS. Whereas caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were detected in wild-type mice at 4 and 5.5 h after GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1(-/-) mice. Delayed development of apoptosis was associated with an extension of survival by 1 h in egr-1(-/-) compared with wild-type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis, and subsequent mortality in GalN/LPS-induced acute liver injury.
Pritchard
Michele T
MT
Dept. of Pathobiology, Cleveland Clinic, 9500 Euclid Ave. NE40, Cleveland, OH 44195, USA. pritchm@ccf.org
Roychowdhury
Sanjoy
S
McMullen
Megan R
MR
Guo
Luping
L
Arteel
Gavin E
GE
Nagy
Laura E
LE
D000818:Animals; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005260:Female; D005688:Galactosamine; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D008070:Lipopolysaccharides; D005688:Galactosamine