scholarly journals Human Herpesvirus 8 Interleukin-6 (vIL-6) Signals through gp130 but Has Structural and Receptor-Binding Properties Distinct from Those of Human IL-6

1999 ◽  
Vol 73 (10) ◽  
pp. 8268-8278 ◽  
Author(s):  
Xiaoyu Wan ◽  
Hailin Wang ◽  
John Nicholas
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Receptor Binding ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Body Cavity ◽  
Human Herpesvirus 8 ◽  
Binding Properties ◽  
Herpesvirus 8 ◽  
Functional Studies

ABSTRACT Human herpesvirus 8 (HHV-8) has been associated with classical, endemic (African), and AIDS-related Kaposi’s sarcoma (KS), body cavity-based primary effusion lymphomas, and multicentric Castleman’s disease (MCD). HHV-8 encodes a functional homologue of interleukin-6 (IL-6), a cytokine that promotes the growth of KS and myeloma cells and is found at elevated levels in MCD lesions and patient sera. We have previously reported that the viral IL-6 (vIL-6) gene product can support the growth of the IL-6-dependent murine hybridoma cell line, B9, and that the gp80 (IL-6 receptor [IL-6R]) component of the IL-6 receptor-signal transducer (gp180) complex plays a role in mediating this activity. However, it has been shown by others that vIL-6 can function in human cells independently of IL-6R. Here we have extended our functional studies of vIL-6 by identifying transcription factors and pathways used in human Hep3B cells, investigating the utilization of gp130 and IL-6R by vIL-6, and undertaking mutational analyses of vIL-6 and gp130. The data presented here establish that vIL-6, in common with its endogenous counterparts, can mediate signal transduction through gp130 and activate multiple transcription factors, map residues within the vIL-6 protein that are and are not important for vIL-6 signalling, and identify a gp130 mutant that is nonfunctional with respect to vIL-6 signalling in the absence of IL-6R but that retains the ability to mediate vIL-6 and human IL-6 (hIL-6) signal transduction when IL-6R is coexpressed. The data presented demonstrate functional and mechanistic similarities between vIL-6 and endogenous IL-6 proteins but also highlight differences in the structural and receptor-binding properties of vIL-6 relative to its human counterpart.

Human interleukin-6 induces human herpesvirus-8 replication in a body cavity-based lymphoma cell line

2002 ◽  
Vol 68 (3) ◽  
pp. 404-411 ◽  
Author(s):  
Jian Song ◽  
Takako Ohkura ◽  
Masamichi Sugimoto ◽  
Yasuko Mori ◽  
Reiko Inagi ◽  
...  
Keyword(s):  
Cell Line ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Body Cavity ◽  
Lymphoma Cell ◽  
Human Herpesvirus 8 ◽  
Lymphoma Cell Line ◽  
Herpesvirus 8

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

2008 ◽  
Vol 83 (2) ◽  
pp. 722-733 ◽  
Author(s):  
Daming Chen ◽  
Gordon Sandford ◽  
John Nicholas
Keyword(s):  
Signal Transduction ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Α Subunit ◽  
Lytic Gene ◽  
Growth And Survival ◽  
Herpesvirus 8 ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT 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 α-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.

scholarly journals Signal Transduction by Human Herpesvirus 8 Viral Interleukin-6 (vIL-6) IsModulated by the Nonsignaling gp80 Subunit of the IL-6 Receptor Complex and Is Distinct from Signaling Induced by Human IL-6

2006 ◽  
Vol 80 (21) ◽  
pp. 10874-10878 ◽  
Author(s):  
Fang Hu ◽  
John Nicholas
Keyword(s):  
Signal Transduction ◽  
Cell Growth ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Receptor Complex ◽  
Α Subunit ◽  
Herpesvirus 8 ◽  
Exogenous Addition ◽  
Growth Promoting

ABSTRACT Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) mediates signaling through the gp130 signal transducer but unlike human IL-6 (hIL-6) does not require the nonsignaling gp80 α subunit of the IL-6 receptor complex. By utilizing a gp80-refractory vIL-6 variant, vIL-6(R189L), we found that signal transduction, as measured by STAT1 and STAT3 activation and gp130 tyrosine phosphorylation in gp80+/gp130+ HEK293T cells, was modulated by gp80. Furthermore, the signaling and BAF-130 cell growth-promoting activities of vIL-6 and hIL-6 could be distinguished, and exogenous addition of soluble gp80 enhanced cell growth supported by vIL-6. Our findings demonstrate that gp80 can modulate vIL-6 activity and that vIL-6 and hIL-6 signaling are not directly equivalent.

scholarly journals Human Herpesvirus 8 Interleukin-6 Interacts with Calnexin Cycle Components and Promotes Protein Folding

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Daming Chen ◽  
Qiwang Xiang ◽  
John Nicholas
Keyword(s):  
Signal Transduction ◽  
Protein Folding ◽  
Membrane Protein ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Infected Cells ◽  
Productive Replication ◽  
Er Membrane

ABSTRACT Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase and signal transducer and activator of transcription signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). The latter functional axis involves suppression of proapoptotic lysosomal protein cathepsin D by promotion of the ER-associated degradation of ER-transiting, preproteolytically processed procathepsin D. Other interactions of VKORC1v2 and activities of vIL-6 via the receptor have not been reported. We show here that both vIL-6 and VKORC1v2 interact with calnexin cycle proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), which catalyzes monoglucosylation of N-glycans, and oppositely acting glucosidase II (GlucII), and that vIL-6 can promote protein folding. This activity was found to require VKORC1v2 and UGGT1, to involve vIL-6 associations with VKORC1v2, UGGT1, and GlucII, and to operate in the context of productively infected cells. These findings document new VKORC1v2-associated interactions and activities of vIL-6, revealing novel mechanisms of vIL-6 function within the ER compartment. IMPORTANCE HHV-8 vIL-6 prosurvival (latent) and proreplication functions are mediated from the ER compartment through both gp130 receptor-mediated signal transduction and interaction of vIL-6 with the ER membrane protein VKORC1v2. This report identifies interactions of vIL-6 and VKORC1v2 with calnexin cycle enzymes GlucII and UGGT1, which are involved in glycan processing and nascent protein folding. The presented data show that vIL-6 and VKORC1v2 can cocomplex with GlucII and UGGT1, that vIL-6 promotes protein folding, and that VKORC1v2, UGGT1, and vIL-6 interactions with GlucII and UGGT1 are important for the profolding activity of vIL-6, which can be detected in the context of infected cells. This newly identified ER activity of vIL-6 involving VKORC1v2 may promote viral latency (in PEL cells) and productive replication by limiting the damaging effects of unfolded protein response signaling in addition to enhancing viral protein folding. This is the first report of such a function for a cytokine.

Association of Primary Pleural Effusion Lymphoma of T-Cell Origin and Human Herpesvirus 8 in a Human Immunodeficiency Virus–Seronegative Man

2001 ◽  
Vol 125 (9) ◽  
pp. 1246-1248 ◽  
Author(s):  
Emmanuèle Lechapt-Zalcman ◽  
Dominique Challine ◽  
Marie-Hélène Delfau-Larue ◽  
Corinne Haioun ◽  
Dominique Desvaux ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Dna Sequences ◽  
Primary Effusion Lymphoma ◽  
Polymerase Chain Reaction Amplification ◽  
Human Herpesvirus ◽  
Body Cavity ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Immunodeficiency Virus

Abstract We describe a case of an 87-year-old human immunodeficiency virus (HIV)–negative man who developed a primary pleural lymphoma without any identifiable tumor mass associated with human herpesvirus 8 (HHV-8) infection. A large T-cell lymphoma was diagnosed based on morphologic, immunophenotypic, and molecular findings. The HHV-8 DNA sequences were detected using specific polymerase chain reaction amplification in the lymphomatous effusion. Study of the patient's serum confirmed the HHV-8 infection. This case report displays the characteristic features of HHV-8–related body cavity-based lymphoma/primary effusion lymphoma previously reported in HIV-seronegative patients, except that it is of T-cell origin. Whether this case may be included or not within the primary effusion lymphoma entity, the association of a pleural T-cell non-Hodgkin lymphoma with HHV-8 infection raises the question of the possible occurrence of T cells as the target of malignant transformation associated with HHV-8 infection.

Human herpesvirus 8-encoded interleukin-6 homologue (viral IL-6) induces endogenous human IL-6 secretion

2000 ◽  
Vol 61 (3) ◽  
pp. 332-335 ◽  
Author(s):  
Yasuko Mori ◽  
Norihiro Nishimoto ◽  
Mika Ohno ◽  
Reiko Inagi ◽  
Panadda Dhepakson ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8

scholarly journals Genetic Analyses of Contributions of Viral Interleukin-6 Interactions and Signaling to Human Herpesvirus 8 Productive Replication

2020 ◽  
Vol 94 (19) ◽  
Author(s):  
Qian Li ◽  
Qiwang Xiang ◽  
Daming Chen ◽  
John Nicholas
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Interactions ◽  
Interleukin 6 ◽  
Kaposi's Sarcoma ◽  
Castleman’S Disease ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Signal Transducer ◽  
Herpesvirus 8 ◽  
Productive Replication

ABSTRACT Human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) is a cytokine that is poorly secreted and localized largely to the endoplasmic reticulum (ER). It has been implicated, along with other HHV-8 proinflammatory and/or angiogenic viral proteins, in HHV-8-associated Kaposi’s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD), in addition to an MCD-related disorder involving systemic elevation of proinflammatory cytokines, including vIL-6 and human IL-6 (hIL-6). In these diseases, lytic (productive) replication, in addition to viral latency, is believed to play a critical role. Proreplication activity of vIL-6 has been identified experimentally in PEL and endothelial cells, but the relative contributions of different vIL-6 interactions have not been established. Productive interactions of vIL-6 with the IL-6 signal transducer, gp130, can occur within the ER, but vIL-6 also interacts in the ER with a nonsignaling receptor called vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2), calnexin, and VKORC1v2- and calnexin-associated proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) and glucosidase II (GlucII). Here, we report the systematic characterization of interaction-altered vIL-6 variants and the lytic phenotypes of recombinant viruses expressing selected variants. Our data identify the critical importance of vIL-6 and its ER-localized activity via gp130 to productive replication in inducible SLK (epithelial) cells, absence of detectable involvement of vIL-6 interactions with VKORC1v2, GlucII, or UGGT1, and the insufficiency and lack of direct contributory effects of extracellular signaling by vIL-6 or hIL-6. These findings, obtained through genetics-based approaches, complement and extend previous analyses of vIL-6 activity. IMPORTANCE Human herpesvirus 8 (HHV-8)-encoded viral interleukin-6 (vIL-6) was the first viral IL-6 homologue to be identified. Experimental and clinical evidence suggests that vIL-6 is important for the onset and/or progression of HHV-8-associated endothelial-cell and B-cell pathologies, including AIDS-associated Kaposi’s sarcoma and multicentric Castleman’s disease. The protein is unusual in its poor secretion from cells and its intracellular activity; it interacts, directly or indirectly, with a number of proteins beyond the IL-6 signal transducer, gp130, and can mediate activities through these interactions in the endoplasmic reticulum. Here, we report the characterization with respect to protein interactions and signal-transducing activity of a panel of vIL-6 variants and utilization of HHV-8 mutant viruses expressing selected variants in phenotypic analyses. Our findings establish the importance of vIL-6 in HHV-8 productive replication and the contributions of individual vIL-6-protein interactions to HHV-8 lytic biology. This work furthers understanding of the biological significance of vIL-6 and its unique intracellular interactions.

Human herpesvirus 8-encoded interleukin 6 activates HIV-1 in the U1 monocytic cell line

AIDS ◽  
1999 ◽  
Vol 13 (14) ◽  
pp. 1851-1855 ◽  
Author(s):  
Julia R. Gage ◽  
Elizabeth Crabb Breen ◽  
Angela Echeverri ◽  
Larry Magpantay ◽  
Tadamitsu Kishimoto ◽  
...  
Keyword(s):  
Cell Line ◽  
Interleukin 6 ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Herpesvirus 8 ◽  
Hiv 1

Human herpesvirus-8-positive body cavity-based lymphoma involving the atria of the heart

2002 ◽  
Vol 11 (4) ◽  
pp. 244-247 ◽  
Author(s):  
Irina Maric ◽  
Stanley Washington ◽  
Arnold Schwartz ◽  
Vasuki Anandan ◽  
Donald S Karcher
Keyword(s):  
Human Herpesvirus ◽  
Body Cavity ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8

Practical Management of Castleman's Disease

2016 ◽  
Vol 136 (1) ◽  
pp. 16-22
Author(s):  
Musa Fares Alzahrani ◽  
Mansoor Radwi ◽  
Heather A. Leitch
Keyword(s):  
Hiv Infection ◽  
Interleukin 6 ◽  
Lymphoproliferative Disorder ◽  
Treatment Options ◽  
Castleman’S Disease ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Castleman's Disease ◽  
Herpesvirus 8 ◽  
Hiv Negative

Castleman's disease (CD) is a rare lymphoproliferative disorder that is most commonly present in multicentric (MCD) form in association with HIV infection. Interleukin-6 (IL-6) and human herpesvirus-8 (HHV-8) play major roles in MCD pathogenesis. Important treatment options have recently become available, particularly with the introduction of IL-6 and IL-6 receptor inhibitors for the treatment of HIV-negative patients with MCD. Though advances in therapy may improve outcomes in some patients, the prognosis remains guarded, and a stratified approach to the management of MCD is needed.

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