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确定对外来抗原和过敏原反应的必要条件。因此，细胞因子的作用在发育和细胞内都受到严格的调节。细胞因子信号抑制蛋白（SOCS）家族代表了一类新的细胞质负反馈调节I型和II型细胞因子。SOCS-1是多种信号通路的关键调节因子，包括那些由细胞因子激活的调节免疫球蛋白重链类转化为IgE的信号通路。SOCS-1可以抑制IFN-3（减少IgE产生）和IL-4（促进IgE产生）的作用。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基因突变小鼠的分析表明，随着SOCS-1等位基因的缺失，IgE水平升高。这表明SOCS-1在体内是IgE的抑制剂。对474名哮喘患者进行了遗传关联研究，以确定SOCS-1位点的遗传变异是否与IgE水平改变相关。研究发现，SOCS-1基因中一种新型单核苷酸多态性（SNP）的携带者血清IgE水平明显低于该等位基因的纯合子。分析表明，该SNP与SOCS-1启动子-820位置的SNP处于连锁不平衡状态。启动子SNP增加了SOCS-1启动子的转录活性。与这一观察结果一致，启动子序列中这种多态性的存在消除了阴阳-1的结合，而阴阳-1被认为是SOCS-1转录活性的负调节因子。这些数据表明，这个细胞因子信号传导关键调控因子的启动子的遗传变异可能影响IgE的产生。我们建议扩展这些数据，以确定SOCS-1位点的多态性如何影响SOCS-1基因表达，以及可变水平的SOCS-1改变小鼠和人类IgE水平的机制。小鼠和人类的遗传数据表明，SOCS-1是IgE水平的抑制剂。该应用程序提出了一系列实验来确定SOCS-1抑制IgE的机制，以及人类SOCS-1位点的遗传变异如何影响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.