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Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-κB activation

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Abstract

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-κB-binding site and is associated with increased binding of classical NF-κB pathway subunits p65, c-Rel and p50, respectively. IL-8 production is defective in K13 mutants defective in classical NF-κB 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-κB 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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Acknowledgements

We thank Dr Andrew Keates for the IL-8 reporter constructs and Drs Inder Verma, Michael Karin and Richard Gaynor for the IKKs-deficient MEF cells. This work was supported by a grant from the National Institutes of Health (R01 CA85177) and the Mario Lemieux Foundation.

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA

    Q Sun, H Matta, G Lu & P M Chaudhary

  2. Division of Hematology-Oncology and the Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    H Matta & P M Chaudhary

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  1. Q Sun
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  2. H Matta
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  4. P M Chaudhary
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Correspondence to P M Chaudhary.

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Sun, Q., Matta, H., Lu, G. et al. Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-κB activation. Oncogene 25, 2717–2726 (2006). https://doi.org/10.1038/sj.onc.1209298

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