Abstract
Lymphoma cells infected with Kaposi's sarcoma-associated herpesvirus are autocrine dependent on virus-derived interleukin-6 (IL-6), but not on cellular IL-6. During viral infection, host cells induce the antiviral factor interferon (IFN) to up-regulate p21, initiate cell cycle arrest, and inhibit virus replication. Viral IL-6, however, blocks IFN signaling. A viral transcriptional program exists in which only the viral IL-6 gene is directly activated by IFN-alpha, allowing the virus to modify its cellular environment by sensing and responding to levels of intracellular IFN signaling. The human cytokine cannot mimic this effect because IFN-alpha down-regulates the IL-6 receptor, gp80. Viral IL-6 bypasses the gp80 regulatory checkpoint by binding directly to the gp130 transducer molecule, resulting in tumor cell autocrine dependence on the viral cytokine for proliferation and survival.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Autocrine Communication
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Cell Division*
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Cytokine Receptor gp130
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Down-Regulation
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Feedback, Physiological
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Genes, Viral
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Herpesvirus 8, Human / genetics
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Herpesvirus 8, Human / immunology
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Herpesvirus 8, Human / physiology*
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Humans
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Interferon-alpha / pharmacology
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Interferon-alpha / physiology*
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Interleukin-6 / genetics
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Interleukin-6 / physiology*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mutation
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Promoter Regions, Genetic
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / metabolism
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Signal Transduction
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription, Genetic
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Tumor Cells, Cultured
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Up-Regulation
Substances
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Antigens, CD
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IL6ST protein, human
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Interferon-alpha
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Interleukin-6
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Membrane Glycoproteins
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Receptors, Interleukin-6
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interleukin-6 receptor alpha
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Cytokine Receptor gp130
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Tetradecanoylphorbol Acetate