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Journal of Virology, January 2007, p. 309-318, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01411-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of CXCL-8 (Interleukin-8) Induction by Double-Stranded RNA Signaling Pathways during Hepatitis C Virus Infection{triangledown}

Jessica Wagoner,1 Michael Austin,1 Jamison Green,1 Tadaatsu Imaizumi,4 Antonella Casola,5 Allan Brasier,5 Khalid S. A. Khabar,6 Takaji Wakita,7 Michael Gale Jr.,8 and Stephen J. Polyak1,2,3*

Departments of Laboratory Medicine,1 Microbiology,2 Pathobiology, University of Washington, Seattle, Washington,3 Hirosaki University School of Medicine, Hirosaki, Japan,4 Departments of Pediatrics and Medicine, University of Texas Medical Branch, Galveston, Texas,5 Program in BioMolecular Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia,6 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan,7 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas8

Received 5 July 2006/ Accepted 5 October 2006

Hepatitis C virus (HCV) infection induces the {alpha}-chemokine interleukin-8 (CXCL-8), which is regulated at the levels of transcription and mRNA stability. In the current study, CXCL-8 regulation by double-stranded (ds)RNA pathways was analyzed in the context of HCV infection. A constitutively active mutant of the retinoic acid-inducible gene I (RIG-I), RIG-N, activated CXCL-8 transcription. Promoter mutagenesis experiments indicated that NF-{kappa}B and interferon (IFN)-stimulated response element (ISRE) binding sites were required for the RIG-N induction of CXCL-8 transcription. IFN-ß promoter stimulator 1 (IPS-1) expression also activated CXCL-8 transcription, and mutations of the ISRE and NF-{kappa}B binding sites reduced and abrogated CXCL-8 transcription, respectively. In the presence of wild-type RIG-I, transfection of JFH-1 RNA or JFH-1 virus infection of Huh7.5.1 cells activated the CXCL-8 promoter. Expression of IFN regulatory factor 3 (IRF-3) stimulated transcription from both full-length and ISRE-driven CXCL-8 promoters. Chromatin immunoprecipitation assays demonstrated that IRF-3 and NF-{kappa}B bound directly to the CXCL-8 promoter in response to virus infection and dsRNA transfection. RIG-N stabilized CXCL-8 mRNA via the AU-rich element in the 3' untranslated region of CXCL-8 mRNA, leading to an increase in its half-life following tumor necrosis factor alpha induction. The data indicate that HCV infection triggers dsRNA signaling pathways that induce CXCL-8 via transcriptional activation and mRNA stabilization and define a regulatory link between innate antiviral and inflammatory cellular responses to virus infection.

* Corresponding author. Mailing address: University of Washington, Virology 359690, 325 9th Avenue, Seattle, WA 98104-2499. Phone: (206) 341-5224. Fax: (206) 341-5203. E-mail: polyak{at}u.washington.edu.

{triangledown} Published ahead of print on 11 October 2006.

Journal of Virology, January 2007, p. 309-318, Vol. 81, No. 1
0022-538X/07/$08.00+0     doi:10.1128/JVI.01411-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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