Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner

Gastroenterology. 2010 Jun;138(7):2509-18, 2518.e1. doi: 10.1053/j.gastro.2010.03.008. Epub 2010 Mar 12.

Abstract

Background & aims: The generation of oxidative stress and transforming growth factor beta1 (TGF-beta1) production play important roles in liver fibrogenesis. We have previously shown that hepatitis C virus (HCV) increases hepatocyte TGF-beta1 expression. However, the mechanisms by which this induction occurs have not been well studied. We explored the possibility that HCV infection regulates TGF-beta1 expression through the generation of reactive oxygen species (ROS), which act through > or =1 of the p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor kappaB (NFkappaB) signaling pathways to induce TGF-beta1 expression.

Methods: We used small molecule inhibitors and short interfering RNAs to knock down these pathways to study the mechanism by which HCV regulates TGF-beta1 production in the infectious JFH1 model.

Results: We demonstrated that HCV induces ROS and TGF-beta1 expression. We further found that JFH1 induces the phosphorylation of p38MAPK, JNK, ERK, and NFkappaB. We also found that HCV-mediated TGF-beta1 enhancement occurs through a ROS-induced and p38 MAPK, JNK, ERK1/2, NFkappaB-dependent pathway.

Conclusions: These findings provide further evidence to support the hypothesis that HCV enhances hepatic fibrosis progression through the generation of ROS and induction of TGF-beta1. Strategies to limit the viral induction of oxidative stress appear to be warranted to inhibit fibrogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Hepacivirus / pathogenicity*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / physiology
  • NF-kappa B / physiology*
  • Oxidative Stress
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Transforming Growth Factor beta1 / biosynthesis*
  • Transforming Growth Factor beta1 / genetics
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Transforming Growth Factor beta1
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases