Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells

J Thromb Haemost. 2015 Jan;13(1):142-54. doi: 10.1111/jth.12789. Epub 2014 Dec 11.


Background: Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown.

Objectives: This study investigated the role of PS in acute alcoholic hepatitis.

Methods: A mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol.

Results: The levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared with WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls.

Conclusions: The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.

Keywords: alcoholism; anticoagulants; hepatitis; natural killer T cells; protein S.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Antigens, CD1d / immunology
  • Antigens, CD1d / metabolism
  • Apoptosis
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Coculture Techniques
  • Disease Models, Animal
  • Ethanol
  • Fatty Liver, Alcoholic / immunology
  • Fatty Liver, Alcoholic / metabolism
  • Fatty Liver, Alcoholic / pathology
  • Hepatitis, Alcoholic / genetics
  • Hepatitis, Alcoholic / immunology
  • Hepatitis, Alcoholic / metabolism*
  • Hepatitis, Alcoholic / pathology
  • Hepatitis, Alcoholic / prevention & control
  • Hepatocytes / immunology
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Humans
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Liver / immunology
  • Liver / metabolism*
  • Liver / pathology
  • Lymphocyte Activation*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism*
  • Protein S / genetics
  • Protein S / metabolism*
  • RNAi Therapeutics
  • Severity of Illness Index
  • Signal Transduction
  • Up-Regulation


  • Antibodies, Neutralizing
  • Antigens, CD1d
  • Blood Proteins
  • CD1d antigen, mouse
  • Inflammation Mediators
  • PROS1 protein, human
  • Protein S
  • Ethanol