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Journal of Virology, August 2005, p. 9725-9734, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9725-9734.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Stimulates the Expression of Cyclooxygenase-2 via Oxidative Stress: Role of Prostaglandin E2 in RNA Replication

Gulam Waris and Aleem Siddiqui*

Department of Microbiology and Program in Molecular Biology, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, Colorado 80262

Received 29 November 2004/ Accepted 5 April 2005

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-{kappa}B mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca2+ chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E2 (PGE2), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE2 levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3ß and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE2 in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.

* Corresponding author. Current address: Department of Medicine, Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Dr., #0803, La Jolla, CA 92130-0803. Phone: (585) 822-1750. Fax: (585) 822-1749. E-mail: asiddiqu{at}ucsd.edu.

Journal of Virology, August 2005, p. 9725-9734, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9725-9734.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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