期刊
CLINICAL SCIENCE
卷 130, 期 20, 页码 1793-1806出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20160400
关键词
acetaminophen toxicity; chemokines; cytokines; LPS; macrophages; inflammation; non-alcoholic steatohepatitis
资金
- Italian Ministry for Research [projects Progetti di Ricerca di Interesse Nazionale (PRIN)]
- Italian Ministry for Research [Fondo per gli Investimenti della Ricerca di Base (FIRB)]
- European Community [HEALTH-F2-2009-241762]
- Foundation Cariplo
- CRT (Cassa di Risparmio di Torino)
Berberine (BRB) is commonly used in herbal medicine, but its mechanisms of action are poorly understood. In the present study, we tested BRB in steatohepatitis induced by a methionine-and choline-deficient (MCD) diet, in acute acetaminophen intoxication and in cultured murine macrophages. BRB markedly improved parameters of liver injury and necroinflammation induced by the MCD diet, although increased mortality was observed by mechanisms independent of bacterial infections or plasma levels of BRB. The MCD diet induced up-regulation of all components of the NLRP3 (NACHT, LRR and PYD domain-containing protein 3) inflammasome, and increased hepatic levels of mature IL-1 beta (interleukin 1 beta). All of these parameters were significantly reduced in mice treated with BRB. In mice administered an acetaminophen overdose, a model dependent on inflammasome activation, BRB reduced mortality and ALT (alanine aminotransferase) elevation, and limited the expression of inflammasome components. In vitro, LPS (lipopolysaccharide)-induced activation of NLRP3 inflammasome in RAW264.7 murine macrophages was markedly decreased by pre-incubation with BRB. BRB significantly limited the activation of the purinergic receptor P2X(7), involved in the late phases of inflammasome activation. Upon P2X(7) knockdown, the ability of BRB to block LPS-induced secretion of IL-1 beta was lost. These data indicate that administration of BRB ameliorates inflammation and injury in two unrelated murine models of liver damage. We demonstrate for the first time that BRB interferes with activation of the NLRP3 inflammasome pathway in vivo and in vitro, through a mechanism based on interference with activation of P2X(7), a purinergic receptor involved in inflammasome activation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据