Quercetin prevents LPS-induced high-mobility group box 1 release and proinflammatory function

Daolin Tang, Rui Kang, Weimin Xiao, Huali Zhang, Michael T. Lotze, Haichao Wang, Xianzhong Xiao

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

The pathogenesis of sepsis is mediated in part by the pathogen-associated molecular pattern molecule bacterial endotoxin, which stimulates macrophages to sequentially release early (e.g., TNF-α, IL-1β) and late (e.g., high-mobility group box [HMGB] 1 protein) proinflammatory mediators. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation into development of several new experimental therapeutics that limit release, either blocking HMGB1 itself or its nominal receptors. Quercetin was recently identified as an experimental therapeutic that significantly protects against oxidative injury. Here, we report that quercetin attenuates lethal systemic inflammation caused by endotoxemia, even if treatment is started after the early TNF response. Quercetin treatment reduced circulating levels of HMGB1 in animals with established endotoxemia. In macrophage cultures, quercetin inhibited release as well as the cytokine activities of HMGB1, including limiting the activation of mitogen-activated protein kinase and NFκB, two signaling pathways that are critical for HMGB1-induced subsequent cytokine release. Quercetin and autophagic inhibitor, wortmannin, inhibited LPS-induced type-II microtubule-associated protein 1A/1B-light chain 3 production and aggregation, as well as HMGB1 translocation and release, suggesting a potential association between autophagy and HMGB1 release. Quercetin delivery, a strategy to pharmacologically inhibit HMGB1 release that is effective at clinically achievable concentrations, now warrants further evaluation in sepsis and other systemic inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)651-660
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume41
Issue number6
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Keywords

  • Autophagy
  • High-mobility group box 1
  • Quercetin
  • Sepsis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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