Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-kappaB activation.
Human herpesvirus 8 (HHV-8) encodes a viral FLICE inhibitory protein (vFLIP), called K13, with homology to the prodomain of caspase 8. K13 has been postulated to protect virally infected cells against death receptor-induced apoptosis. We report that K13 leads to constitutive upregulation of IL-8 secretion by transcriptional upregulation of its promoter. K13-induced IL-8 promoter activation is dependent on an intact NF-kappaB-binding site and is associated with increased binding of classical NF-kappaB pathway subunits p65, c-Rel and p50, respectively. IL-8 production is defective in K13 mutants defective in classical NF-kappaB activation and is blocked by genetic and pharmacological inhibitors of this pathway. In contrast, K13 failed to activate the JNK/AP-1 pathway and deletion of AP-1-binding site in the IL-8 promoter or use of a specific JNK inhibitor had only a partial effect on K13-induced IL-8 promoter activation. Collectively, above results demonstrate that K13 is a major mediator of IL-8 production and therapeutic agents targeting K13-induced NF-kappaB pathway may have a role in the treatment of conditions in which HHV-8-induced IL-8 production plays a pathogenic role.
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Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
Matta
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Lu
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Chaudhary
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D001665:Binding Sites; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000494:pharmacology*
D016209:Interleukin-8; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D008156:Luciferases; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D048670:MAP Kinase Kinase 4