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

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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 2007

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Hepatitis C virus
Double-Stranded RNA
interleukin-8
double-stranded RNA
Virus Diseases
Interleukin-8
Hepacivirus
transcription (genetics)
promoter regions
response elements
Response Elements
Interferon Regulatory Factor-3
infection
retinoic acid
interferons
transfection
Tretinoin
viruses
Messenger RNA
Interferons

ASJC Scopus subject areas

  • Immunology

Cite this

Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. / Wagoner, Jessica; Austin, Michael; Green, Jamison; Imaizumi, Tadaatsu; Casola, Antonella; Brasier, Allan; Khabar, Khalid S A; Wakita, Takaji; Gale, Michael; Polyak, Stephen J.

In: Journal of Virology, Vol. 81, No. 1, 01.2007, p. 309-318.

Research output: Contribution to journalArticle

Wagoner, J, Austin, M, Green, J, Imaizumi, T, Casola, A, Brasier, A, Khabar, KSA, Wakita, T, Gale, M & Polyak, SJ 2007, 'Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection', Journal of Virology, vol. 81, no. 1, pp. 309-318. https://doi.org/10.1128/JVI.01411-06
Wagoner, Jessica ; Austin, Michael ; Green, Jamison ; Imaizumi, Tadaatsu ; Casola, Antonella ; Brasier, Allan ; Khabar, Khalid S A ; Wakita, Takaji ; Gale, Michael ; Polyak, Stephen J. / Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. In: Journal of Virology. 2007 ; Vol. 81, No. 1. pp. 309-318.
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