title: Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.
abstract: Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.
authors.affiliation: Liver Institute, Beilinson Hospital-Rabin Medical Center, Petah Tiqwa, Israel. gbenari@bezeqint.net
authors.forename: Ziv
authors.initials: Z
authors.lastname: Ben Ari
authors.forename: Orna
authors.initials: O
authors.lastname: Avlas
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Veacheslav
authors.initials: V
authors.lastname: Zilbermints
authors.forename: Yelena
authors.initials: Y
authors.lastname: Cheporko
authors.forename: Larissa
authors.initials: L
authors.lastname: Bachmetov
authors.forename: Romy
authors.initials: R
authors.lastname: Zemel
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.forename: Eran
authors.initials: E
authors.lastname: Sharon
authors.forename: Franklin
authors.initials: F
authors.lastname: Grief
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005688:Galactosamine / Q000494:pharmacology; D053583:Interleukin-1beta / Q000032:analysis / Q000097:blood; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000097:blood
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3