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， 急性或慢性接触乙醇会损害肝再生 部分肝切除术或化学性肝损伤，但其机制 乙醇通过何种方式抑制肝再生尚不清楚。最近的 在缺乏白细胞介素 6 (il-6) 的“基因敲除”小鼠中获得的证据 表明信号转导器的 IL-6 激活和激活 转录蛋白 3 (Stat3) 的表达是肝脏中的关键步骤 再生。初步实验表明，急性治疗 乙醇可以阻断IL-诱导的大鼠肝脏中Stat3的激活 6 体外或体内部分肝切除术。这些发现表明 乙醇的抗再生作用至少部分是介导的， 通过阻断 IL-6 诱导的 Stat3 激活。其机制 乙醇抑制 IL-6 诱导的 Stat3 激活将通过以下方式进行探索 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 与其相互作用 受体、gp130 蛋白和 IL-6- 的酪氨酸磷酸化 诱导 JAK 激酶的激活。长期摄入乙醇对身体的影响 将探讨 IL-6 或部分肝切除术诱导的 Stat3 激活 在维持含乙醇流质饮食的大鼠中。鉴定 由乙醇调节的 IL 信号通路不仅会增强我们的 对酒精性肝病发病机制的了解 也可能揭示乙醇对其他信号系统的影响 组织，例如大脑。