HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 2012 May 31;119(22):5173-81
Date
04/12/2012Pubmed ID
22490805Pubmed Central ID
PMC3370672DOI
10.1182/blood-2011-09-377705Scopus ID
2-s2.0-84861851475 (requires institutional sign-in at Scopus site) 103 CitationsAbstract
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.
Author List
Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W, Tosato G, Janz S, Scheller J, Rose-John SAuthor
Siegfried Janz MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCastleman Disease
Cytokine Receptor gp130
Herpesviridae Infections
Herpesvirus 8, Human
Histocompatibility Antigens Class I
Humans
Interleukin-6
Mice
Mice, Transgenic
Promoter Regions, Genetic
Viral Proteins