Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 6, Pages 2830-2836Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300157
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Funding
- Collaborative Research Center of the Deutsche Forschungsgemeinschaft [SFB796]
- Forschung und Lehre im Klinikum (ELAN) fund of the Friedrich-Alexander University Erlangen-Nuremberg
- Medical Research Council [U117527252]
- MRC [MC_U117527252] Funding Source: UKRI
- Medical Research Council [MC_U117527252] Funding Source: researchfish
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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.
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