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易感性，其特征在于 免疫系统细胞对正常细胞因子反应的破坏。的NFkB 转录因子家族是细胞因子应答的关键调节因子， 协调对免疫刺激的转录反应。初步数据 表明乙醇特异性抑制了 两种不同的NFkB复合物。乙醇会抑制信号 诱导NF κ B抑制剂IkappaB α的磷酸化，从而阻断 NF κ B的核转位和NF κ B的激活反应 基因.一种新的、活化的Bcl-3/p50复合物的形成也受到抑制 在乙醇的存在下。提出了一种实验策略， 重点关注乙醇抑制IkappaB α磷酸化的机制。 NFkB信号通路对乙醇的敏感性取决于 细胞类型和特异性诱导剂，使用 几种良好表征的细胞模型和激活方案将有助于 乙醇调节的上游激活事件的鉴定。 初步数据显示，乙醇抑制了最近的 表征了IkappaB激酶复合物及其上游调节因子MEKK 1。这些 将扩大和加强研究，以确定分子靶点， 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。为了衡量 NFkB对乙醇免疫抑制的影响，乙醇对NFkB的影响， 诱导剂对细胞刺激的反应 NFkB将被量化。待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。平行实验 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 应该允许NFkB抑制对免疫系统的功能性后果， 系统将被预测和测试更高的精度。

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.