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Journal of Virology, January 2009, p. 722-733, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01517-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intracellular Signaling Mechanisms and Activities of Human Herpesvirus 8 Interleukin-6

Daming Chen, Gordon Sandford, and John Nicholas^*

Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Received 18 July 2008/ Accepted 27 October 2008

Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) has been implicated as a key factor in virus-associated neoplasia because of its proproliferative and survival effects and also in view of its angiogenic properties. A major difference between vIL-6 and human IL-6 (hIL-6) is that vIL-6, uniquely, is largely retained and can signal intracellularly. While vIL-6 is generally considered to be a lytic gene, several reports have noted its low-level expression in latently infected primary effusion lymphoma (PEL) cultures, in the absence of other lytic gene expression. Thus, intracellular autocrine signal transduction by the viral cytokine may be of particular relevance to the growth and survival of latently infected cells and to pathogenesis. Here we report that most intracellular vIL-6 is located in the endoplasmic reticulum (ER), signals via the gp130 signal transducer in this compartment, and does so independently of the gp80 -subunit of the IL-6 receptor, required for hIL-6 signal transduction. Signaling and biological assays incorporating ER-retained vIL-6 and hIL-6 confirmed vIL-6 activity, specifically, in this compartment. Knockdown of vIL-6 expression in PEL cells led to markedly reduced cell growth in normal culture, independently of extracellular cytokines. This could be reversed by reintroduction via virus vector of exclusively ER-retained vIL-6. These data indicate that in virus biology vIL-6 may act to support the growth and survival of cells latently infected with HHV-8 in an autocrine manner via intracrine signaling and that these activities may contribute to the maintenance of latently infected cells and to virus-induced neoplasia.

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* Corresponding author. Mailing address: Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. Phone: (410) 502-6801. Fax: (410) 502-6802. E-mail: nichojo{at}jhmi.edu

Published ahead of print on 5 November 2008.

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Journal of Virology, January 2009, p. 722-733, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01517-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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