The Analyses of th Mechanism of IgE Production by Interleukin-4

过敏性疾病是一种多因素遗传性疾病，其遗传因素称为特应性。已知诱导IgE产生的IL-4和IL-13在变应性疾病的发病机制中具有关键作用。在这项研究中，我探讨了IL-4受体α链（IL-4 R α），这是由LL-4 R和IL-13 R共享，是一个特应性致病基因的可能性。结果表明，1）在特应性哮喘患者中，在JL-4 R α的第50位氨基酸处的异亮氨酸的发生率高于缬氨酸的发生率，2）IL-4信号在异亮氨酸型转染的B细胞系中比在缬氨酸型转染的细胞系中更多地被转导，3）异亮氨酸型外周血单核细胞比缬氨酸型产生更多的IgE。这些结果表明IL-4 R α的Ile 50 Val取代可能导致特应性。我确定了IL-4 R α激活STAT 6的关键部分，并发现p47 α<phox>与该部分结合。提示P47是<phox>IL-4的一种新的信号转导分子。已知IL-4存在一种选择性剪接产物IL-4 δ 2。IL-4 δ 2本身并不阻断IL-4信号，而是作为T细胞上IL-4的竞争性抑制剂。我分析了IL-4 δ 2对其他类型细胞的作用，发现IL-4 δ 2不仅在T细胞上，而且在B细胞和单核细胞上作为IL-4的竞争性抑制剂。这些结果为重组IL-4 δ 2作为过敏性患者的治疗试剂的潜在用途创造了背景。

Allergic diseases are multifactorial inheritable diseases, and their genetic factor is called atopy. It is known that IL-4 and IL-13 which induce IgE production have a pivotal role in pathogenesis of allergic disease. I explored the possibility that the IL-4 receptor alpha chain (IL-4R alpha), which is shared by both LL-4R and IL-13R, is a atopy-causing gene, in this study. As a result, it turned out that 1) in atopic asthma patients, the incidence of isoleucine at 50th amino acid of JL-4R alpha was higher that that of valine, 2) the IL-4 signals were tranduced more in the isoleucine type-transfected B cell lines than the valine type, 3) the isoleucine type peripheral blood mononuclear cells generated more IgE than the valine type. These results suggest that Ile50Val substitution of IL-4R alpha could cause atopy.It is known that STAT6 is a transcription factor important for the 11-4 signals. I identified the critical portion of IL-4R alpha for STAT6 activation, and found that p47^<phox> binds to this portion. These results indicate that is P47^<phox> a new signal-transducing molecule of 11-4.It is known that there exists an alternative splicing product of IL-4, IL-4delta2. IL-4delta2 itself does not transduce the IL-4 signals, and acts as a competitive inhibitor against IL-4 on T cells. I analyzed the effects of IL-4delta2 on other kinds of cells, and found that IL-4delta2 acts as a competitive inhibitor against IL-4 on not only T cells, but also B cells and monocytes. These results create the background for the potential use of recombinant IL-4delta2 as a therapeutic reagent for allergic patients.