HHV-8–encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice

Jan Suthaus; Christiane Stuhlmann-Laeisz; Van S Tompkins; Timothy R Rosean; Wolfram Klapper; Giovanna Tosato; Siegfried Janz; Jürgen Scheller; Stefan Rose-John

doi:10.1182/blood-2011-09-377705

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HHV-8–encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice

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HHV-8–encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice

Jan Suthaus, Christiane Stuhlmann-Laeisz, Van S Tompkins, Timothy R Rosean, Wolfram Klapper, Giovanna Tosato, Siegfried Janz, Jürgen Scheller and Stefan Rose-John

Blood, Vol.119(22), pp.5173-5181

05/31/2012

DOI: 10.1182/blood-2011-09-377705

PMCID: PMC3370672

PMID: 22490805

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Abstract

Human herpes virus 8 (HHV-8) or Kaposi sarcoma-associated herpes virus is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and plasma cell-type multicentric Castleman disease (MCD). HHV-8 encodes a viral homolog of human IL-6, called viral IL-6 (vIL-6), which does not require the cellular IL-6 receptor for binding to the ubiquitously expressed gp130 receptor subunit and subsequent JAK-STAT signaling. Thus, in contrast to IL-6, vIL-6 can stimulate virtually all cells in the body. To elucidate the mechanism by which vIL-6 drives human diseases, we generated transgenic mice that constitutively express vIL-6 under control of the MHC class I promoter. The mice were found to exhibit vIL-6 serum levels comparable with those observed in HHV-8–infected patients, to contain elevated amounts of phosphorylated STAT3 in spleen and lymph nodes, where vIL-6 was produced, and to spontaneously develop key features of human plasma cell-type MCD, including splenomegaly, multifocal lymphadenopathy, hypergammaglobulin-emia, and plasmacytosis. Transfer of the vIL-6 transgene onto an IL-6 –deficient genetic background abrogated MCD-like phenotypes, indicating that endogenous mouse IL-6 is a crucial cofactor in the natural history of the disease. Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8–associated MCD.

Immunobiology

Details

Title: Subtitle: HHV-8–encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice
Creators: Jan Suthaus - Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
Christiane Stuhlmann-Laeisz - Institute of Pathology, Christian-Albrechts-University, Kiel, Germany
Van S Tompkins - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA
Timothy R Rosean - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA
Wolfram Klapper - Institute of Pathology, Christian-Albrechts-University, Kiel, Germany
Giovanna Tosato - Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and
Siegfried Janz - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA
Jürgen Scheller - Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Stefan Rose-John - Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
Resource Type: Journal article
Publication Details: Blood, Vol.119(22), pp.5173-5181
DOI: 10.1182/blood-2011-09-377705
PMID: 22490805
PMCID: PMC3370672
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: American Society of Hematology
Grant note: R01CA151354; T32-HL07734; 5T32AI007485-17 / National Institutes of Health
Language: English
Date published: 05/31/2012
Academic Unit: Pathology
Record Identifier: 9984083232902771

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