ETHANOL AND IL6 SIGNAL TRANSDUCTION

乙醇和 IL6 信号转导

• 批准号: 2558838
• 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
• 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/2558838
• 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

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，如果酒精引起的肝毒性的结果 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后，会损害肝脏再生 部分肝切除术或化学诱导的肝损伤，但机制 乙醇抑制肝脏再生仍然未知。最近的 在白介素6（IL-6）缺乏的“敲除”小鼠中获得的证据 表明信号传感器的IL-6激活和激活 转录蛋白3（STAT3）是肝脏的关键步骤 再生。初步实验表明，急性治疗 乙醇可以阻止大鼠肝脏中Stat3的激活，由IL-诱导 6体外或部分肝切除术。这些发现表明 乙醇的抗再生作用至少部分地介导 通过阻断IL-6诱导的STAT3激活。该机制 乙醇抑制IL-6诱导的STAT3激活将由 分析急性乙醇处理对IL-6诱导的影响 信号转导级联，包括IL-6与其的相互作用 受体，GP130蛋白和IL-6-的酪氨酸磷酸化 诱导的jak激酶的激活。慢性乙醇对 将探索由IL-6或部分肝切除术引起的STAT3激活 在维持含乙醇的液体饮食的大鼠中。识别 由乙醇调节的IL信号途径不仅会增强我们的 了解酒精诱发的肝病的发病机理，但 还可以阐明乙醇对其他信号系统的影响 组织，例如大脑。