Treatment with HMGB1 inhibitors diminishes CTL-induced liver disease in HBV transgenic mice

Research output: Contribution to journalArticle

Abstract

Using hepatitis B virus (HBV) transgenic mice as recipients of virus-specific cytotoxic T lymphocytes (CTLs), we recently showed that polymorphonuclear neutrophils (PMNs) and the matrix-degrading metalloproteinases (MMPs) they produce are necessary for the intrahepatic recruitment of antigen nonspecific mononuclear cells that amplify the liver damage initiated by the CTLs. We now report that the high-mobility group box 1 protein (HMGB1) is also involved in this process. Transfer of CTLs in HBV transgenic mice induces the translocation of HMGB1 from the nucleus to the cytoplasm of hepatocytes surrounding CTL-containing necroinflammatory liver foci, without significant net synthesis of HMGB1. Treatment of CTL-injected HBV transgenic mice with either recombinant Box-A or glycyrrhizin, two functional inhibitors of extracellular HMGB1, significantly decreases the intrahepatic recruitment of PMNs and all other inflammatory cells, in the face of intact homing of virus-specific CTLs into the liver. The inhibition of PMN chemoattraction explains the mode of action of glycyrrhizin, which has long been used in Japan for the treatment of hepatitis, and suggests that new and more potent inhibitors of HMGB1 may be useful for the treatment of patients chronically infected with HBV.

Original languageEnglish
Pages (from-to)100-107
Number of pages8
JournalJournal of Leukocyte Biology
Volume81
Issue number1
DOIs
Publication statusPublished - Jan 2007

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HMGB1 Protein
Cytotoxic T-Lymphocytes
Hepatitis B virus
Transgenic Mice
Liver Diseases
Glycyrrhizic Acid
Liver
Neutrophils
Therapeutics
Viruses
Neutrophil Infiltration
Matrix Metalloproteinases
Hepatitis
Hepatocytes
Japan
Cytoplasm
Antigens

Keywords

  • Immunopathology
  • Inflammation
  • Liver infection
  • Tissue damage

ASJC Scopus subject areas

  • Cell Biology

Cite this

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abstract = "Using hepatitis B virus (HBV) transgenic mice as recipients of virus-specific cytotoxic T lymphocytes (CTLs), we recently showed that polymorphonuclear neutrophils (PMNs) and the matrix-degrading metalloproteinases (MMPs) they produce are necessary for the intrahepatic recruitment of antigen nonspecific mononuclear cells that amplify the liver damage initiated by the CTLs. We now report that the high-mobility group box 1 protein (HMGB1) is also involved in this process. Transfer of CTLs in HBV transgenic mice induces the translocation of HMGB1 from the nucleus to the cytoplasm of hepatocytes surrounding CTL-containing necroinflammatory liver foci, without significant net synthesis of HMGB1. Treatment of CTL-injected HBV transgenic mice with either recombinant Box-A or glycyrrhizin, two functional inhibitors of extracellular HMGB1, significantly decreases the intrahepatic recruitment of PMNs and all other inflammatory cells, in the face of intact homing of virus-specific CTLs into the liver. The inhibition of PMN chemoattraction explains the mode of action of glycyrrhizin, which has long been used in Japan for the treatment of hepatitis, and suggests that new and more potent inhibitors of HMGB1 may be useful for the treatment of patients chronically infected with HBV.",
keywords = "Immunopathology, Inflammation, Liver infection, Tissue damage",
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AU - Sitia, Giovanni

AU - Iannacone, Matteo

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AU - Bianchi, Marco E.

AU - Guidotti, Luca G.

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