Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection

Jessica Wagoner, Michael Austin, Jamison Green, Tadaatsu Imaizumi, Antonella Casola, Allan Brasier, Khalid S.A. Khabar, Takaji Wakita, Michael Gale, Stephen J. Polyak

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Hepatitis C virus (HCV) infection induces the α-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-κB and interferon (IFN)-stimulated response element (ISRE) binding sites were required for the RIG-N induction of CXCL-8 transcription. IFN-β promoter stimulator 1 (IPS-1) expression also activated CXCL-8 transcription, and mutations of the ISRE and NF-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)309-318
Number of pages10
JournalJournal of virology
Volume81
Issue number1
DOIs
StatePublished - Jan 1 2007

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Wagoner, J., Austin, M., Green, J., Imaizumi, T., Casola, A., Brasier, A., Khabar, K. S. A., Wakita, T., Gale, M., & Polyak, S. J. (2007). Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. Journal of virology, 81(1), 309-318. https://doi.org/10.1128/JVI.01411-06