This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0119OCv1 41/6/651    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tang, D. Articles by Xiao, X. PubMed PubMed Citation Articles by Tang, D. Articles by Xiao, X.

Quercetin Prevents LPS-Induced High-Mobility Group Box 1 Release and Proinflammatory Function

¹ Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine; ² Department of Pediatrics, Xiangya Hospital; Central South University, Changsha, Hunan, People's Republic of China; ³ College of Optometry, University of Houston, Houston, Texas; ⁴ Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ⁵ Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, New York

Correspondence and requests for reprints should be addressed to Xianzhong Xiao, M.D., Ph.D., Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, P.R. China. E-mail: xianzhongxiao{at}xysm.net or Haichao Wang, Ph.D., at hwang{at}nshs.edu

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-, 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 NF-B, 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.

Key Words: quercetin • high-mobility group box 1 • sepsis • autophagy

CLINICAL RELEVANCE Quercetin delivery, a strategy to pharmacologically inhibit high-mobility group box 1 release that is effective at clinically achievable concentrations, now warrants further evaluation in sepsis and other systemic inflammatory disorders.