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

描述：酒精引起的免疫抑制，表现为 对细菌和病毒感染的敏感性，其特点是 免疫系统细胞对正常细胞因子反应的干扰。NFkB 转录因子家族是细胞因子反应的关键调节因子， 协调对免疫刺激的转录反应。初步数据 证明了乙醇可以特异性地抑制细胞的激活 髓系细胞系中存在两种不同的NFkB复合体。乙醇抑制这种信号 诱导NFkB抑制剂IkappaBalpha的磷酸化，从而阻断 NFkB向细胞核的移位及激活NFkB反应 基因。此外，还抑制了一种新的、激活的Bcl3/p50复合体的形成 在乙醇存在的情况下。提出了一种试验性策略，它将 重点研究乙醇抑制IkappaBalpha磷酸化的机制。 NFkB信号通路对乙醇的敏感性因 细胞类型和特定诱导剂，比较使用 几个特性良好的细胞模型和激活协议将有助于 乙醇调节的上游激活事件的识别。 初步数据显示，乙醇可抑制新近激活的 鉴定了IkappaB激酶复合体及其上游调控因子MEKK1。这些 将扩大和加强研究，以确定分子靶标或 乙醇与NFkB信号通路的相互作用。类似的战略 将被应用于Bcl3/p50激活通路。以衡量其重要性 NFkB对乙醇免疫抑制作用的影响 诱导剂对细胞刺激的诱导分化和激活 NFkB将被量化。有待研究的参数包括标记蛋白 表达、生长停滞、细胞黏附和吞噬。平行实验 将检测酒精敏感性对NFkB靶基因表达的影响，包括 细胞因子、抗凋亡蛋白和病毒启动子。所获得的数据 应该允许抑制NFkB对免疫的功能后果 更准确地预测和测试系统。

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.