title: KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) encodes a structural and functional homologue of human IL-6 called viral IL-6 (vIL-6). Expression of vIL-6 in KSHV-related lymphoproliferative disorders has been implicated in their pathogenesis. vIL-6 has been shown to mimic a number of IL-6 activities including stimulating the growth of IL-6 dependent cell lines and activating the JAK1 and STAT1/3 pathway in HepG2 cells. However, IL-6 and vIL-6 display differences in receptor usage that may give rise to underlying qualitative and quantitative differences in the signaling pathways utilized. While IL-6 has an absolute requirement for both the IL-6 Ralpha and the gp130 subunits, vIL-6 appears to require only gp130. In addition to JAK1 and STAT1/3 pathways, IL-6 activates multiple other pathways including the direct activation of STAT 5 by JAK1, the Ras-MAP kinase cascade and a novel H7-sensitive pathway. In this study we examined whether vIL-6 is capable of signaling via distinct IL-6 response elements (IL-6 RE) under the control of these different pathways. We show that vIL-6 activates both STAT1/3- and STAT5-dependent Type II IL-6 REs. In addition, vIL-6 induces transcriptional activation via a Type I IL-6 RE that binds C/EBP, indicative of Ras-MAP kinase pathway induction. Furthermore, vIL-6 is capable of activating the IL-6 response element in the c-jun promoter (RE-IL-6). vIL-6 induced activation of JRE-IL-6 requires both the Ets- and Cre-like sites, suggesting that vIL-6 is capable of stimulating the same novel serine/threonine kinase mediated pathway as IL-6. These results demonstrate that vIL-6 can stimulate all of the known IL-6-induced signaling pathways. Therefore, vIL-6 could potentially contribute to KSHV-related disease progression by continued activation of IL-6-stimulated growth and anti-apoptotic pathways even when cells attempt to protect themselves from IL-6 over-stimulation by downmodulating their IL-6Ralpha subunits.
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10027, USA.
authors.forename: J
authors.initials: J
authors.lastname: Osborne
authors.forename: P S
authors.initials: PS
authors.lastname: Moore
authors.forename: Y
authors.initials: Y
authors.lastname: Chang
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D020935:MAP Kinase Signaling System; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D020218:Response Elements; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000494:pharmacology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D014157:Transcription Factors; D014764:Viral Proteins