Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models

Abstract

Withaferin A (WFA), an active compound from Withania somnifera, is widely researched for its anti- inflammatory, cardioactive and central nervous system effects. In this study, we first investigated the possible barrier protective effects of WFA against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice induced by high mobility group box 1 protein (HMGB1) and the associated sig- naling pathways. The barrier protective activities of WFA were determined by measuring permeability, leu- kocytes adhesion and migration, and activation of pro-inflammatory proteins in HMGB1-activated HUVECs. We found that WFA inhibited lipopolysaccharide (LPS)-induced HMGB1 release and HMGB1-mediated barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of leukocytes to human endothelial cells. WFA also suppressed acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed thatWFA suppressed the production of interleukin 6, tumor necrosis factor-α (TNF-α) and activation of nuclear factor-κB (NF-κB) by HMGB1. Collectively, these results suggest that WFA protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its useful- ness as a therapy for vascular inflammatory diseases. © 2012 Elsevier Inc. All rights reserved. Keywords: Withaferin A HMGB1 Endothelium Inflammation Barrier integrity