Role of SOCS-1 in Regulation of IgE

描述(由申请人提供)：细胞因子作用的大小和持续时间是决定对外来抗原和过敏原的反应的关键。因此，细胞因子的活动在发育过程中和细胞内都受到严格的调控。细胞因子信号转导抑制因子(SOCS)蛋白家族代表了一组新的I型和II型细胞因子的胞质负反馈调节因子。SOCS-1是多种信号通路的关键调节者，包括那些由细胞因子激活的信号通路，这些细胞因子调节免疫球蛋白重链类向IgE的转换。SOCS-1可抑制干扰素-3和白介素4的作用，干扰素-3减少IgE的产生，IL-4促进IgE的产生。因此，SOCS-1水平的差异如何影响IgE水平和特应性免疫反应尚不清楚。对SOCS-1基因突变的小鼠的分析表明，随着SOCS-1等位基因的丧失，IgE水平增加。提示SOCS-1在体内是一种免疫球蛋白E的抑制因子。对474名哮喘患者进行了一项遗传关联研究，以确定SOCS-1基因座的遗传变异是否与IgE水平的变化有关。SOCS-1基因的一种新的单核苷酸多态(SNP)携带者与该等位基因纯合子相比，血清IgE水平显著降低。分析表明，该SNP与SOCS-1启动子-820位的SNP存在连锁不平衡。启动子SNP增加了SOCS-1启动子的转录活性。与此观察一致的是，启动子序列中这种多态的存在取消了阴阳-1的结合，阴阳-1被认为是SOCS-1转录活性的负调控因子。这些数据表明，这种关键的细胞因子信号调节因子启动子的遗传变异可能会影响IgE的产生。我们建议扩展这些数据，以确定SOCS-1基因的多态如何影响SOCS-1基因的表达，以及不同水平的SOCS-1改变小鼠和人类的IgE水平的机制。与公共健康相关的小鼠和人类的遗传数据表明，SOCS-1是一种IgE水平的抑制物。这项申请提出了一系列实验，以确定SOCS-1抑制IgE的机制，以及人类SOCS-1基因变异如何影响IgE水平。

DESCRIPTION (provided by applicant): The magnitude and the duration of cytokine action are essential in determining the response to foreign antigens and allergens. Thus, the action of cytokines is tightly regulated both developmentally and within the cell. The Suppressor of Cytokine Signaling (SOCS) protein family represents a novel group of cytoplasmic negative feedback regulators of type I and II cytokines. SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate immunoglobulin heavy chain class switching to IgE. SOCS-1 can inhibit the action of IFN-3, which decreases IgE production, and IL-4, which promotes IgE production. Therefore, how differences in SOCS-1 levels would affect IgE levels and atopic immune responses was unclear. Analysis of mice with mutations in the SOCS-1 gene demonstrates that with loss of SOCS-1 alleles the levels of IgE increase. This suggests that SOCS-1 is an inhibitor of IgE in vivo. A genetic association study was performed in 474 asthmatics to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of a novel, single nucleotide polymorphism (SNP) in the SOCS-1 gene were found to have significantly lower levels of serum IgE as compared with homozygotes for the allele. Analysis demonstrated that this SNP was in linkage disequilibrium with a SNP at position -820 of the SOCS-1 promoter. The promoter SNP increases transcriptional activity of the SOCS-1 promoter. Consistent with this observation, the presence of this polymorphism within the promoter sequence abolished binding of Yin-Yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the promoter of this key regulator of cytokine signaling may affect IgE production. We propose to extend these data to determine how polymorphisms of the SOCS-1 locus affect SOCS-1 gene expression and the mechanism by which variable levels of SOCS-1 alter IgE levels in both mice and humans. PUBLIC HEALTH RELEVANCE Genetic data in mice and humans suggest that SOCS-1 is an inhibitor of IgE levels. This application proposes a series of experiments to determine the mechanisms by which SOCS-1 inhibits IgE and how genetic variants in the human SOCS-1 locus affect IgE levels.