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Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection.
Title | Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Wagoner, J, Austin, M, Green, J, Imaizumi, T, Casola, A, Brasier, A, Khabar, KSA, Wakita, T, Gale, M, Polyak, SJ |
Journal | J Virol |
Volume | 81 |
Issue | 1 |
Pagination | 309-18 |
Date Published | 2007 Jan |
ISSN | 0022-538X |
Keywords | Cell Line, DEAD-box RNA Helicases, Gene Expression Regulation, Hepacivirus, Humans, Interferon Regulatory Factor-3, Interleukin-8, Mutation, Promoter Regions, Genetic, RNA, Double-Stranded, RNA, Messenger, Signal Transduction, Transcription, Genetic |
Abstract | 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-kappaB and interferon (IFN)-stimulated response element (ISRE) binding sites were required for the RIG-N induction of CXCL-8 transcription. IFN-beta promoter stimulator 1 (IPS-1) expression also activated CXCL-8 transcription, and mutations of the ISRE and NF-kappaB 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-kappaB 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. |
DOI | 10.1128/JVI.01411-06 |
Alternate Journal | J. Virol. |
PubMed ID | 17035306 |