Role of SOCS-1 in Regulation of IgE

描述（由申请方提供）：细胞因子作用的幅度和持续时间对于确定对外源抗原和过敏原的应答至关重要。因此，细胞因子的作用在发育过程中和细胞内都受到严格的调节。细胞因子信号转导抑制因子（Suppressor of Cytokine Signaling，SOCS）蛋白家族是一类新型的I型和II型细胞因子胞质负反馈调节因子。SOCS-1是多种信号传导途径的关键调节剂，包括由调节免疫球蛋白重链类别转换为IgE的细胞因子激活的信号传导途径。SOCS-1可以抑制IFN-3和IL-4的作用，IFN-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水平和特应性免疫应答尚不清楚。对SOCS-1基因突变小鼠的分析表明，随着SOCS-1等位基因的丢失，IgE水平增加。这表明SOCS-1是体内IgE的抑制剂。在474名哮喘患者中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水平的改变相关。发现SOCS-1基因中一种新的单核苷酸多态性（SNP）的携带者与等位基因的纯合子相比，血清IgE水平显着降低。分析表明，该SNP与SOCS-1启动子-820位点的SNP连锁不平衡。启动子SNP增加SOCS-1启动子的转录活性。与这一观察结果一致，启动子序列内这种多态性的存在消除了Yin-Yang-1的结合，Yin-Yang-1被鉴定为SOCS-1转录活性的负调节因子。这些数据表明，这种细胞因子信号传导的关键调节因子的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基因座的多态性如何影响SOCS-1基因表达，以及SOCS-1的可变水平改变小鼠和人类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。本申请提出了一系列实验来确定SOCS-1抑制IgE的机制以及人SOCS-1基因座中的遗传变体如何影响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.