A key regulatory role of Vav1 in controlling LPS endotoxemia via macrophage derived IL-6
| Autor: | Zenker, Stefanie, Panteleev-Ivlev, Julia, Wirtz, Stefan, Kishimoto, Tadamitsu, Waldner, Maximilian J., Ksionda, Olga, Tybulewicz, Victor L. J., Neurath, Markus F., Atreya, Imke |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Lipopolysaccharides
Mice Knockout Mice Inbred BALB C Microscopy Confocal Interleukin-6 Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Macrophages Blotting Western Gene Expression Kaplan-Meier Estimate Macrophage Activation Article Endotoxemia Interleukin-10 DNA-Binding Proteins Mice Inbred C57BL Mice Heat Shock Transcription Factors Animals Proto-Oncogene Proteins c-vav Cells Cultured Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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