Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo

High mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Rutin (RT), an active flavonoid compound, is well known to possess potent antiplatelet, antiviral and antihypertensive properties. In this study, we investigated the anti-inflammatory effects of RT against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by HMGB1 and the associated signaling pathways. The anti-inflammatory activities of RT were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs and mice. We found that RT potently inhibited HMGB1 release, down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with RT resulted in reduced cecal ligation and puncture-induced release of HMGB1 and sepsis-related mortality. Further studies revealed that RT suppressed the production of tumor necrosis factor-alpha and interleukin 6 and the activation of nuclear factor-kappa B and extracellular regulated kinases 1/2 by HMGB1. Collectively, these results indicate that RT could be a candidate therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.