Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner.
OBJECTIVE
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.
Lin
Wenyu
W
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Tsai
Wei-Lun
WL
Shao
Run-Xuan
RX
Wu
Guoyang
G
Peng
Lee F
LF
Barlow
Lydia L
LL
Chung
Woo Jin
WJ
Zhang
Leiliang
L
Zhao
Hong
H
Jang
Jae-Young
JY
Chung
Raymond T
RT
D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases