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

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• 作者：Wonhwa Lee^a ; ^b ; ¹ ; Tae Hoon Kim^c ; ¹ ; Sae-Kwang Ku^d ; ¹ ; Kyoung-jin Min^e ; Hyun-Shik Lee^f ; Taeg Kyu Kwon^e ; Jong-Sup Bae^a ; ^{baejs@knu.ac.kr}
• 关键词：WFA ; withaferin A ; HMGB1 ; high mobility group box 1 protein ; HUVEC ; human umbilical vein endothelial cell ; CAM ; cell adhesion molecule ; TNF-伪 ; tumor necrosis factor-伪 ; NF-魏B ; nuclear factor-魏B ; EC ; endothelial cell ; LPS ; lipopolysaccharide ; VCAM ; vasc
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 期刊代码：58_0041008x
• 类别：pha
• 出版时间：1 July, 2012
• 卷：262
• 期：1
• 页码：91-98
• 文件大小：655 K

摘要

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 signaling pathways. The barrier protective activities of WFA were determined by measuring permeability, leukocytes 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 that WFA suppressed the production of interleukin 6, tumor necrosis factor-伪 (TNF-伪) and activation of nuclear factor-魏B (NF-魏B) 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 usefulness as a therapy for vascular inflammatory diseases.