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Journal of Virology, June 2005, p. 7648-7657, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7648-7657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Core Protein Suppresses NF-{kappa}B Activation and Cyclooxygenase-2 Expression by Direct Interaction with I{kappa}B Kinase ß

Myungsoo Joo,1* Young S. Hahn,2 Minjae Kwon,1 Ruxana T. Sadikot,1 Timothy S. Blackwell,1 and John W. Christman1

Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, and Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232,1 Department of Microbiology and Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 229082

Received 30 July 2004/ Accepted 25 January 2005

In addition to hepatocytes, hepatitis C virus (HCV) infects immune cells, including macrophages. However, little is known concerning the impact of HCV infection on cellular functions of these immune effector cells. Lipopolysaccharide (LPS) activates I{kappa}B kinase (IKK) signalsome and NF-{kappa}B, which leads to the expression of cyclooxygenase-2 (COX-2), which catalyzes production of prostaglandins, potent effectors on inflammation and possibly hepatitis. Here, we examined whether expression of HCV core interferes with IKK signalsome activity and COX-2 expression in activated macrophages. In reporter assays, HCV core inhibited NF-{kappa}B activation in RAW 264.7 and MH-S murine macrophage cell lines treated with bacterial LPS. HCV core inhibited IKK signalsome and IKKß kinase activities induced by tumor necrosis factor alpha in HeLa cells and coexpressed IKK{gamma} in 293 cells, respectively. HCV core was coprecipitated with IKKß and prevented nuclear translocation of IKKß. NF-{kappa}B activation by either LPS or overexpression of IKKß was sufficient to induce robust expression of COX-2, which was markedly suppressed by ectopic expression of HCV core. Together, these data indicate that HCV core suppresses IKK signalsome activity, which blunts COX-2 expression in macrophages. Additional studies are necessary to determine whether interrupted COX-2 expression by HCV core contributes to HCV pathogenesis.

* Corresponding author. Mailing address: Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2650. Phone: (615) 343-2365. Fax: (615) 343-7748. E-mail: myungsoo.joo{at}vanderbilt.edu.

Journal of Virology, June 2005, p. 7648-7657, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7648-7657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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