Synergistic effects of antibodies against high-mobility group box 1 and tumor necrosis factor-α antibodies on D-(+)-galactosamine hydrochloride/lipopolysaccharide-induced acute liver failure

FEBS J. 2013 Mar;280(6):1409-19. doi: 10.1111/febs.12132. Epub 2013 Feb 14.


High-mobility group box 1 (HMGB1) protein is released into the serum after tissue damage, and serves as a warning signal to enhance the inflammatory response. Acute liver injury is one of the diseases that starts with tissue damage and ends with systemic inflammation. We used D-(+)-galactosamine hydrochloride (D-GalN)/lipopolysaccharide (LPS)-treated mice as an acute liver injury model to explore the functions of HMGB1 in more detail. HMGB1 is released into the serum at a very early stage of D-GalN/LPS-induced acute liver injury. It upregulates the expression of tumor necrosis factor-α (TNF-α), interleukin-6, inducible nitric oxide synthase, and tissue factor. TNF-α and HMGB1 form a positive feedback loop to amplify the downstream signals. mAbs against HMGB1 and TNF-α have synergistic effects in protecting mice from D-GalN/LPS-induced acute liver failure. The results suggest that HMGB1 is a key mediator in D-GalN/LPS-induced acute liver injury. Tissue damage and cell necrosis shortly after administration of D-GalN and LPS lead to early HMGB1 release, and HMGB1 acts synergistically with TNF-α to promote pathological processes in acute liver failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Chemical and Drug Induced Liver Injury / drug therapy
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / pathology*
  • Drug Synergism
  • Female
  • Galactosamine / adverse effects
  • HMGB1 Protein / blood
  • HMGB1 Protein / immunology*
  • Immunohistochemistry
  • Interleukin-6 / immunology
  • Lipopolysaccharides / adverse effects
  • Liver / drug effects
  • Liver / immunology
  • Liver / pathology
  • Liver Failure, Acute / drug therapy
  • Liver Failure, Acute / immunology
  • Liver Failure, Acute / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Necrosis / immunology
  • Necrosis / pathology
  • Nitric Oxide Synthase Type II / immunology
  • Protein Interaction Mapping
  • Tumor Necrosis Factor-alpha / immunology*


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • HMGB1 Protein
  • Interleukin-6
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • interleukin-6, mouse
  • Galactosamine
  • Nitric Oxide Synthase Type II
  • Alanine Transaminase