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ETHANOL AND IL6 SIGNAL TRANSDUCTION

乙醇和 IL6 信号转导

基本信息

批准号：
2894248
负责人：
bin gao
金额：
$ 7.25万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-07 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2894248
关键词：
JAK kinase biological signal transduction cytokine receptors ethanol hepatectomy hepatotoxin interleukin 6 laboratory rat liver regeneration pathologic process tissue /cell culture transcription factor

项目摘要

Alcoholic liver disease if the result of alcohol-induced hepatotoxicity coupled with impaired hepatic regenerative capacity. In animal models, acute or chronic exposure to ethanol impairs liver regeneration following partial hepatectomy or chemically induced liver injury, but the mechanisms by which ethanol inhibits liver regeneration are still unknown. Recent evidence obtained in 'knock-out' mice deficient in interleukin-6 (il-6) indicates that activation by IL-6 of the signal transducer and activation of transcription protein 3 (Stat3) is a critical step in liver regeneration. Preliminary experiments have shown that acute treatment with ethanol can block the activation of Stat3 in the rat liver, induced by IL- 6 in vitro or by partial hepatectomy in vivo. These findings suggest that the anti-regenerative effects of ethanol are mediated, at least in part, through blocking IL-6 induced Stat3 activation. The mechanism by which ethanol inhibits IL-6-induced Stat3 activation will be explored by analyzing the effects of acute ethanol treatment on the IL-6-induced signal transduction cascade, including the interaction of IL-6 with its receptor, the tyrosine phosphorylation of the gp130 protein and IL-6- induced activation of the JAK kinases. The effects of chronic ethanol on Stat3 activation induced by IL-6 or partial hepatectomy will be explored in rats maintained on a ethanol-containing liquid diet. Identification of the IL-signaling pathway modulated by ethanol will not only enhance our understanding of the pathogenesis of alcoholic-induced liver disease but may also shed light on the effects of ethanol on signal systems in other tissues such as the brain.

酒精性肝病如果是酒精引起的肝毒性的结果再加上肝脏再生能力受损。在动物模型中，急性或慢性暴露于乙醇损害肝再生部分肝切除术或化学诱导的肝损伤，但机制乙醇是如何抑制肝再生的还不清楚。最近在缺乏白细胞介素-6（il-6）的“基因敲除”小鼠中获得的证据表明IL-6激活信号转导子和激活转录蛋白3（Stat 3）的转录是肝脏中的一个关键步骤，再生初步实验表明，急性治疗与乙醇可阻断IL-2诱导的大鼠肝脏Stat 3的活化。 6体外或体内部分肝切除。这些发现表明乙醇的抗再生作用，至少部分地，通过阻断IL-6诱导的Stat 3活化。的机制乙醇抑制IL-6诱导的Stat 3活化将通过以下方法进行探索：分析急性乙醇治疗对IL-6诱导的信号转导级联，包括IL-6与其受体，gp 130蛋白和IL-6的酪氨酸磷酸化。诱导JAK激酶的活化。慢性酒精对将探讨IL-6或部分肝切除术诱导的Stat 3活化在维持含乙醇液体饮食的大鼠中。鉴定由乙醇调节的IL-信号通路不仅会增强我们的免疫应答，了解酒精性肝病的发病机制，也可能揭示乙醇对其他信号系统的影响，组织，如大脑。