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Journal of Virology, January 2006, p. 866-874, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.866-874.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Induces Toll-Like Receptor 4 Expression, Leading to Enhanced Production of Beta Interferon and Interleukin-6

Keigo Machida,1 Kevin T. H. Cheng,1 Vicky M.-H. Sung,1 Alexandra M. Levine,2 Steven Foung,4 and Michael M. C. Lai1,3*

Department of Molecular Microbiology and Immunology,1 Department of Medicine, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, California 90033,2 Academia Sinica, Taipei 115, Taiwan,3 Department of Pathology, Stanford University Blood Center, 800 Welch Road, Palo Alto, California 943044

Received 7 July 2005/ Accepted 19 October 2005

Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-ß) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-ß and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, USC Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033. Phone: (323) 442-1748. Fax: (323) 442-1721. E-mail: michlai{at}usc.edu.

Journal of Virology, January 2006, p. 866-874, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.866-874.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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