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Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-κB and JNK/AP1 pathways

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Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a FADD-like interferon converting enzyme or caspase 8 (FLICE) inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis by inhibiting the recruitment and activation of FLICE. Since vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF2 mediates activation of the jun NH2-terminal kinase (JNK)/activation protein 1 (AP1) pathway, we hypothesized that vFLIP might also activate this pathway. To evaluate this hypothesis, we transiently and stably transfected a vFLIP expression construct and performed several complementary assays to document that vFLIP activates the JNK/AP1 pathway and does so in a TRAF-dependent fashion. As vFLIP also activates the nuclear factor κB (NF-κB) signaling pathway and the NF-κB and JNK/AP1 pathways both modulate cellular interleukin-6 (cIL-6) expression, we postulated that vFLIP induces expression of this cytokine. We show that vFLIP induces cIL-6 expression and activates the cIL-6 promoter, and maximal activation of the cIL-6 promoter by vFLIP requires NF-κB and AP1 activation. In addition, vFLIP and latency-associated nuclear antigen (LANA), another KSHV-encoded latent protein, potentiate each other's ability to activate the cIL-6 promoter. Gene silencing experiments by RNA interference demonstrate that vFLIP in BCBL-1 endogenously infected primary effusion lymphoma (PEL) cells mediates JNK/AP1 activation and cIL-6 expression. Thus, we conclude that vFLIP, in addition to its known effects on NF-κB activation, also modulates the JNK/AP1 pathway and induces gene expression from the cIL-6 promoter in a JNK/AP1-dependent fashion.

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Acknowledgements

We thank Drs Alan K Lichtenstein and Gregory Brent for their critical review of the manuscript and helpful discussions. Supported by research funds of the Veterans Administration, including a Career Development Award and the VA Research Enhancement Award Program (REAP) (both to MBR), the Jonsson Comprehensive Cancer Center at UCLA (to MBR and RS), the American Cancer Society (Grant # RPG-00-305-01-MBC to MBR), the Public Health Service (Grant # 1R01CA80004-01A1 to MBR), and the American Society of Hematology (Junior Faculty Scholar Award to MBR).

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Authors and Affiliations

  1. Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, 90073, CA, USA

    Jiabin An, Yiping Sun & Matthew B Rettig

  2. Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, 90095, CA, USA

    Ren Sun

  3. Department of Medicine, UCLA School of Medicine, Los Angeles, 90095, CA, USA

    Matthew B Rettig

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  1. Jiabin An
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Correspondence to Matthew B Rettig.

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An, J., Sun, Y., Sun, R. et al. Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-κB and JNK/AP1 pathways. Oncogene 22, 3371–3385 (2003). https://doi.org/10.1038/sj.onc.1206407

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