ROLE OF NF-KB IN THE SUPPRESSION OF IMMUNITY BY ETHANOL

NF-KB 在乙醇抑制免疫中的作用

• 批准号: 6629672
• 负责人: Raphael Rubin
• 金额: $ 27.83万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629672
• 关键词: BCL2 gene /protein; I kappa B beta; cell growth regulation; cell line; cytokine; enzyme activity; ethanol; genetic transcription; immunosuppression; macrophage; nuclear factor kappa beta; phagocytosis; phosphorylation

DESCRIPTION: Immunosuppression by alcohol, manifested by increased susceptibility to bacterial and viral infections, is characterized by the disruption of normal cytokine responses by cells of the immune system. The NFkB family of transcription factors is a critical regulator of cytokine responses, coordinating the transcriptional response to immune stimuli. Preliminary data is presented demonstrating that ethanol specifically inhibits the activation of two distinct NFkB complexes in myeloid cell lines. Ethanol inhibits the signal induced phosphorylation of the NFkB inhibitor IkappaBalpha, thereby blocking the translocation of NFkB to the nucleus and the activation NFkB response genes. The formation of a novel, activated Bcl-3/p50 complex is also inhibited in the presence of ethanol. An experimental strategy is proposed that will focus on the mechanism by which ethanol inhibits IkappaBalpha phosphorylation. The sensitivity of the NFkB signaling pathway to ethanol differs depending on the cell type and the specific inducing agent, comparing the response using several well-characterized cell models and activation protocols will facilitate the identification of the upstream activating events modulated by ethanol. Preliminary data show that ethanol suppresses activation of the recently characterized IkappaB kinase complex, and its upstream regulator MEKK1. These studies will be extended and intensified to identify the molecular target or the interaction of ethanol with the NFkB signaling pathway. A similar strategy will be applied to the Bcl-3/p50 activation pathway. To gauge the significance of NFkB for immunosuppression by ethanol, the effects of ethanol on differentiation and activation in response to cell stimulation by inducers of NFkB will be quantified. Parameters to be studied include marker protein expression, growth arrest, cell adhesion and phagocytosis. Parallel experiments will examine the ethanol sensitivity of NFkB target gene expression, including cytokines, anti-apoptotic proteins, and viral promoters. The data obtained should allow the functional consequences of NFkB inhibition for the immune system to be predicted and tested with greater accuracy.

描述：酒精免疫抑制，表现为增加 对细菌和病毒感染的敏感性的特征是 免疫系统细胞对正常细胞因子反应的破坏。 NFKB 转录因子家族是细胞因子反应的关键调节剂， 协调对免疫刺激的转录反应。初步数据 提出了表明乙醇特异性抑制激活 髓样细胞系中的两个不同的NFKB复合物。乙醇抑制信号 诱导NFKB抑制剂Ikappabalpha的磷酸化，从而阻止 NFKB向细胞核的易位和激活NFKB响应 基因。还抑制了新型活化的Bcl-3/p50复合物的形成 在乙醇的情况下。提出了一种实验策略 侧重于乙醇抑制Ikappabalpha磷酸化的机制。 NFKB信号通路对乙醇的敏感性取决于 细胞类型和特定诱导剂，使用 几种特征良好的细胞模型和激活方案将有助于 鉴定乙醇调节的上游激活事件。 初步数据表明，乙醇抑制最近的激活 Ikappab激酶综合体及其上游调节器MEKK1的特征。这些 研究将扩展并加强以识别分子靶标或 乙醇与NFKB信号通路的相互作用。类似的策略 将应用于BCL-3/P50激活途径。衡量意义 NFKB用于乙醇的免疫抑制，乙醇对 诱导者的细胞刺激响应细胞刺激的分化和激活 NFKB将被量化。要研究的参数包括标记蛋白 表达，生长停滞，细胞粘附和吞噬作用。并行实验 将检查NFKB靶基因表达的乙醇敏感性，包括 细胞因子，抗凋亡蛋白和病毒启动子。获得的数据 应允许NFKB抑制免疫的功能后果 可以更准确地预测和测试的系统。