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Journal of Virology, December 2009, p. 12934-12946, Vol. 83, No. 24
0022-538X/09/$08.00+0     doi:10.1128/JVI.01059-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus (HCV) Proteins Induce NADPH Oxidase 4 Expression in a Transforming Growth Factor β-Dependent Manner: a New Contributor to HCV-Induced Oxidative Stress{triangledown}

Howard E. Boudreau,{dagger} Suzanne U. Emerson,{ddagger} Agnieszka Korzeniowska,{dagger} Meghan A. Jendrysik,{dagger} and Thomas L. Leto*

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland

Received 23 May 2009/ Accepted 26 September 2009

Viral hepatitis-induced oxidative stress accompanied by increased levels of transforming growth factor β (TGF-β) and hepatic fibrosis are hallmarks of hepatitis C virus (HCV) infection. The mechanisms of redox regulation in the pathogenesis of HCV-induced liver disease are not clearly understood. The results of our current studies suggest that reactive oxygen species (ROS) derived from Nox4, a member of the NADPH oxidase (Nox) family, could play a role in HCV-induced liver disease. We found that the expression of HCV (genotype 1a) cDNA constructs (full-length and subgenomic), core protein alone, viral RNA, or replicating HCV (JFH-AM2) induced Nox4 mRNA expression and ROS generation in human hepatocyte cell lines (Huh-7, Huh-7.5, HepG2, and CHL). Conversely, hepatocytes expressing Nox4 short hairpin RNA (shRNA) or an inactive dominant negative form of Nox4 showed decreased ROS production when cells were transfected with HCV. The promoters of both human and murine Nox4 were used to demonstrate transcriptional regulation of Nox4 mRNA by HCV, and a luciferase reporter tied to an ~2-kb promoter region of Nox4 identified HCV-responsive regulatory regions modulating the expression of Nox4. Furthermore, the human Nox4 promoter was responsive to TGF-β1, and the HCV core-dependent induction of Nox4 was blocked by antibody against TGF-β or the expression of dominant negative TGF-β receptor type II. These findings identified HCV as a regulator of Nox4 gene expression and subsequent ROS production through an autocrine TGF-β-dependent mechanism. Collectively, these data provide evidence that HCV-induced Nox4 contributes to ROS production and may be related to HCV-induced liver disease.

* Corresponding author. Present address: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD, 20852. Phone: (301) 402-5120. Fax: (301) 480-1731. E-mail: tleto{at}nih.gov

{triangledown} Published ahead of print on 7 October 2009.

{dagger} Present Address: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.

{ddagger} Present Address: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.

Journal of Virology, December 2009, p. 12934-12946, Vol. 83, No. 24
0022-538X/09/$08.00+0     doi:10.1128/JVI.01059-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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