Viral IL-6-Induced Cell Proliferation and Immune Evasion of Interferon Activity

Chatterjee, Malini; Osborne, Julie; Bestetti, Giovanna; Chang, Yuan; Moore, Patrick S.

doi:10.1126/science.1074883

Cited by 205 publications

(168 citation statements)

References 24 publications

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“…vIL-6 protects virus-infected cells from undergoing growth arrest and apoptosis or cell death, which is one strategy that the immune system applies to limit viral infection. vIL-6 inhibits signaling of the antiviral factor alpha interferon, which prevents virus-infected cells from growing (13). In addition, in some cells, vIL-6 not only stops the suppression of tumors but also causes healthy cells that are not infected with HHV-8 to proliferate abnormally (49).…”

Section: Discussionmentioning

confidence: 99%

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Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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Human herpesvirus 8 (HHV-8) encodes several putative oncogenes, which are homologues to cellular host genes known to function in cell cycle regulation, control of apoptosis, and cytokine signaling. Viral interleukin (vIL-6) is believed to play an important role in the pathogenesis of Kaposi's sarcoma as well as primary effusion lymphoma and multicentric Castleman's disease. Therefore, vIL-6 is a promising target for novel therapies directed against HHV-8-associated diseases. By phage display screening of human synthetic antibody libraries, we have selected a specific recombinant antibody, called monoclonal anti-vIL-6 (MAV), binding to vIL-6. The epitope recognized by MAV was localized on the top of the D helix of the vIL-6 protein, which is a part of receptor binding site III. Consequently, MAV specifically inhibits vIL-6-mediated growth of the primary effusion lymphoma-derived cell line BCBL-1 and blocks STAT3 phosphorylation in the human hepatoma cell line HepG2. Since it was previously found that vIL-6 can also induce signals from within the cell, presumably within the endoplasmic reticulum, we fused the recombinant antibody MAV with the endoplasmic retention sequence KDEL (MAV-KDEL). As a result, COS-7 cells expressing MAV-KDEL and synthesizing vIL-6 ceased to secrete the cytokine. Moreover, we observed that vIL-6 that was bound to MAV-KDEL and retained in the endoplasmic reticulum did not induce STAT3 phosphorylation in HepG2 cells. We conclude that the activity of the intracellularly retained vIL-6 protein is neutralized by MAV-KDEL. Our results might represent a novel therapeutic strategy to neutralize virally encoded growth factors or oncogenes.

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Section: Discussionmentioning

confidence: 99%

“…Viral IL-6 may act as an antiapoptotic factor for the survival of HHV-8-infected cells and/or promote the proliferation of HHV-8-infected cells or potential host cells. In lymphoma cells infected with HHV-8, the viral cytokine protects cells against innate immune defenses triggered by viral infection via blocking of the interferon signaling pathway (13).…”

mentioning

confidence: 99%

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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“…Viruses modulate the TNF family of receptors by producing homologues (Seet et al 2003) and modulate cytokine pathways in natural killer cells (Orange et al 2002). Many more examples have been described for viruses (Guidotti & Chisari 2001;Chatterjee et al 2002;Seet et al 2003), bacteria (Hilbi et al 1997;Hornef et al 2002;Portnoy 2005) or nematodes (Grencis & Entwistle 1997).…”

Section: The Diversity Of Immune Evasion Mechanismsmentioning

confidence: 99%

Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence

Schmid‐Hempel

2008

Phil. Trans. R. Soc. B

207

177

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The discussion of host-parasite interactions, and of parasite virulence more specifically, has so far, with a few exceptions, not focused much attention on the accumulating evidence that immune evasion by parasites is not only almost universal but also often linked to pathogenesis, i.e. the appearance of virulence. Now, the immune evasion hypothesis offers a deeper insight into the evolution of virulence than previous hypotheses. Sensitivity analysis for parasite fitness and life-history theory shows promise to generate a more general evolutionary theory of virulence by including a major element, immune evasion to prevent parasite clearance from the host. Also, the study of dose-response relationships and multiple infections should be particularly illuminating to understand the evolution of virulence. Taking into account immune evasion brings immunological processes to the core of understanding the evolution of parasite virulence and for a range of related issues such as dose, host specificity or immunopathology. The aim of this review is to highlight the mechanism underlying immune evasion and to discuss possible consequences for the evolutionary ecology analysis of host-parasite interactions.

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“…The large number of redundant inhibitors of MHC class I suggests an important role for CTLs in defending against herpesvirus infection. Similarly, many herpesviruses encode proteins that impair type I IFN induction or action (20)(21)(22)(23), and CMV has recently been found to encode proteins that block NK cellactivating receptors (24).…”

Section: Introductionmentioning

confidence: 99%