Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C

J Viral Hepat. 2011 Nov;18(11):760-7. doi: 10.1111/j.1365-2893.2010.01362.x. Epub 2010 Aug 15.

Abstract

Chronic hepatitis C infection leads to increased hepatocyte apoptosis. Because engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) is profibrogenic, we compared the effects of ABs derived from hepatitis C virus (HCV)-negative vs HCV-infected (Con1+) Huh7 hepatoblastoma cells on fibrogenic and activation-related mRNA expression by a human HSC line (LX2). Uptake of Huh7(Con1+) ABs by LX2 cells dose dependently upregulated profibrotic genes (COL1A1, TGFB1; TIMP1; TIMP2). When normalized to the apoptotic cytokeratin-18 M30 neoepitope, HCV(+) ABs exhibited a more pronounced effect than HCV(-) ABs. In contrast, neither noningested ABs nor nucleic acids obtained from Huh7, Huh7(Con1+) or HepG2 cells triggered those AB-dependent effects. Both the engulfment of Huh7(Con1+) ABs and their effects were partially blocked by masking of phosphatidylserine with annexin V and completely inhibited by the class-A scavenger receptor ligand, polyinosinic acid. Our findings demonstrate that AB uptake stimulates HSCs and indicate that HCV infection leads to amplified fibrogenic mRNA expression and enhanced HSC activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Annexin A5 / metabolism
  • Antibodies / metabolism
  • Apoptosis*
  • Cell Line
  • Cell Line, Tumor
  • Collagen Type I / biosynthesis
  • Collagen Type I / genetics
  • Collagen Type I, alpha 1 Chain
  • Hepacivirus / physiology*
  • Hepatic Stellate Cells / pathology*
  • Hepatic Stellate Cells / physiology
  • Hepatitis C Antigens
  • Hepatitis C, Chronic / metabolism
  • Hepatitis C, Chronic / pathology*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology*
  • Hepatocytes / virology
  • Humans
  • Keratin-18 / genetics
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / virology
  • Phosphatidylserines / metabolism
  • Poly I / metabolism
  • RNA, Messenger / biosynthesis
  • Receptor, Platelet-Derived Growth Factor beta / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Transforming Growth Factor beta1 / biosynthesis
  • Transforming Growth Factor beta1 / genetics
  • Viral Nonstructural Proteins*

Substances

  • ACTA2 protein, human
  • Actins
  • Annexin A5
  • Antibodies
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Hepatitis C Antigens
  • Keratin-18
  • Phosphatidylserines
  • RNA, Messenger
  • TGFB1 protein, human
  • TIMP1 protein, human
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta1
  • Viral Nonstructural Proteins
  • Tissue Inhibitor of Metalloproteinase-2
  • Poly I
  • Receptor, Platelet-Derived Growth Factor beta