Viral IL-6-induced cell proliferation and immune evasion of interferon activity.
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.
Chatterjee
Malini
M
Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Osborne
Julie
J
Bestetti
Giovanna
G
Chang
Yuan
Y
Moore
Patrick S
PS
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D002455:Cell Division; D050822:Cytokine Receptor gp130; D015536:Down-Regulation; D025461:Feedback, Physiological; D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015703:Antigens, CD; C494199:IL6ST protein, human; D016898:Interferon-alpha; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D013755:Tetradecanoylphorbol Acetate