title: A key regulatory role for Vav1 in controlling lipopolysaccharide endotoxemia via macrophage-derived IL-6.
abstract: Macrophages are centrally involved in the pathogenesis of acute inflammatory diseases, peritonitis, endotoxemia, and septic shock. However, the molecular mechanisms controlling such macrophage activation are incompletely understood. In this article, we provide evidence that Vav1, a member of the RhoGEF family, plays a crucial role in macrophage activation and septic endotoxemia. Vav1-deficient mice demonstrated a significantly increased susceptibility for LPS endotoxemia that could be abrogated by anti-IL-6R Ab treatment. Subsequent studies showed that Vav1-deficient macrophages display augmented production of the proinflammatory cytokine IL-6. Nuclear Vav1 was identified as a key negative regulator of macrophage-derived IL-6 production. In fact, Vav1 formed a nuclear DNA-binding complex with heat shock transcription factor 1 at the HSE2 region of the IL-6 promoter to suppress IL-6 gene transcription in macrophages. These findings provide new insights into the pathogenesis of endotoxemia and suggest new avenues for therapy.
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zenker
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Panteleev-Ivlev
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Osaka University, Suita City, Japan.
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Waldner
authors.affiliation: MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Ksionda
authors.affiliation: MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Victor L J
authors.initials: VLJ
authors.lastname: Tybulewicz
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Medical Clinic 1, Friedrich-Alexander University of Erlangen-Nürnberg, University Hospital of Erlangen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Atreya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D000076249:Heat Shock Transcription Factors; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051567:Proto-Oncogene Proteins c-vav; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C496619:Vav1 protein, mouse; D016753:Interleukin-10