HMGB1 recruits hepatic stellate cells and liver endothelial cells to sites of ethanol-induced parenchymal cell injury
HMGB1 recruits hepatic stellate cells and liver endothelial cells to sites of ethanol-induced parenchymal cell injury
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DOI：
10.1152/ajpgi.00151.2013
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发表时间：
2013-12-01
影响因子：
4.5
通讯作者：
Shah, Vijay H.
中科院分区：
文献类型：
--
作者：
Seo, Yeon S.;Kwon, Jung H.;Shah, Vijay H.
肝星状细胞（HSC）和肝内皮细胞（LEC）迁移到损伤部位并使酒精诱导的肝损伤持续存在。高迁移率族蛋白1（HMGB 1）是一种从受损细胞核释放的蛋白质，被认为是促炎介质。我们假设HMGB 1可能从乙醇刺激的肝实质细胞中释放出来，并有助于HSC和LEC的募集。用Western blot检测乙醇刺激大鼠肝细胞和HepG 2细胞后HMGB 1从细胞核转位。与溶剂处理的细胞相比，乙醇处理的肝细胞上清液中的HMGB 1蛋白水平增加。乙醇刺激的肝细胞条件培养液（CMEtOH）与溶剂刺激的肝细胞（CMVEH）相比，HSC和LEC的迁移均增加（P < 0.05）。然而，与对照siRNA转染的HepG 2细胞相比，用HMGB 1中和抗体处理或用HMGB 1-siRNA预转染的HepG 2细胞几乎完全逆转了CMEtOH对迁移的影响（P < 0.05）。与载体刺激相比，重组HMGB 1（100 ng/ml）也刺激HSC和LEC的迁移（对于HSC和LEC两者，P < 0.05）。HMGB 1刺激HSC增加Src和Erk的磷酸化，并且HMGB 1诱导的HSC迁移被Src抑制剂PP 2和Erk抑制剂U 0126阻断。肝细胞释放HMGB 1响应于乙醇，随后招募HSC和LEC。这一途径对HSC和LEC向乙醇诱导的肝损伤部位的募集具有意义。
Hepatic stellate cells (HSC) and liver endothelial cells (LEC) migrate to sites of injury and perpetuate alcohol-induced liver injury. High-mobility group box 1 (HMGB1) is a protein released from the nucleus of injured cells that has been implicated as a proinflammatory mediator. We hypothesized that HMGB1 may be released from ethanol-stimulated liver parenchymal cells and contribute to HSC and LEC recruitment. Ethanol stimulation of rat hepatocytes and HepG2 cells resulted in translocation of HMGB1 from the nucleus as assessed by Western blot. HMGB1 protein levels were increased in the supernatant of ethanol-treated hepatocytes compared with vehicle-treated cells. Migration of both HSC and LEC was increased in response to conditioned medium for ethanol-stimulated hepatocytes (CMEtOH) compared with vehicle-stimulated hepatocytes (CMVEH) (P < 0.05). However, the effect of CMEtOH on migration was almost entirely reversed by treatment with HMGB1-neutralizing antibody or when HepG2 cells were pretransfected with HMGB1-siRNA compared with control siRNA-transfected HepG2 cells (P < 0.05). Recombinant HMGB1 (100 ng/ml) also stimulated migration of HSC and LEC compared with vehicle stimulation (P < 0.05 for both HSC and LEC). HMGB1 stimulation of HSC increased the phosphorylation of Src and Erk and HMGB1-induced HSC migration was blocked by the Src inhibitor PP2 and the Erk inhibitor U0126. Hepatocytes release HMGB1 in response to ethanol with subsequent recruitment of HSC and LEC. This pathway has implications for HSC and LEC recruitment to sites of ethanol-induced liver injury.