title: HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice.
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, hypergammaglobulinemia, 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.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Suthaus
authors.forename: Christiane
authors.initials: C
authors.lastname: Stuhlmann-Laeisz
authors.forename: Van S
authors.initials: VS
authors.lastname: Tompkins
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rosean
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
mesh_terms: D000818:Animals; D005871:Castleman Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; C508600:IL6 protein, human; D015850:Interleukin-6; D014764:Viral Proteins; C120140:interleukin-6, RRV-HHV-8; D050822:Cytokine Receptor gp130