title: The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation.
abstract: The predominant tumor cell of Kaposi's Sarcoma (KS) is the spindle cell, a cell of endothelial origin that expresses markers of lymphatic endothelium. In culture, Kaposi's Sarcoma-associated herpesvirus (KSHV) infection of blood endothelial cells drives expression of lymphatic endothelial cell specific markers, in a process that requires activation of the gp130 receptor and the JAK2/STAT3 and PI3K/AKT signaling pathways. While expression of each of the KSHV major latent genes in endothelial cells failed to increase expression of lymphatic markers, the viral homolog of human IL-6 (vIL-6) was sufficient for induction and requires the JAK2/STAT3 and PI3K/AKT pathways. Therefore, activation of gp130 and downstream signaling by vIL-6 is sufficient to drive blood to lymphatic endothelial cell differentiation. While sufficient, vIL-6 is not necessary for lymphatic reprogramming in the context of viral infection. This indicates that multiple viral genes are involved and suggests a central importance of this pathway to KSHV pathogenesis.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Morris
authors.forename: Almira S
authors.initials: AS
authors.lastname: Punjabi
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wells
authors.forename: Cristina J
authors.initials: CJ
authors.lastname: Wittkopp
authors.forename: Richard
authors.initials: R
authors.lastname: Vart
authors.forename: Michael
authors.initials: M
authors.lastname: Lagunoff
mesh_terms: D001773:Blood Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D015398:Signal Transduction; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D014764:Viral Proteins; D050822:Cytokine Receptor gp130; D053614:Janus Kinase 2