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

Interleukin-4产生IgE的机制分析

• 批准号: 09670348
• 负责人: IZUHARA Kenji
• 金额: $ 0.51万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670348/
• 关键词: Interleukin-4; Interleukin-13; Atopy; Allergy; Interleukin-4 Recepter; Cytokine; Signal Transduction; IgE; STAT6

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.

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。

项目成果

H.Niiro: "Regulation by Interleukin-10 and Interleukin-4 of Cyclooxygen ase-2 Expression in Human Neutrophils." Blood. 89. 1621-1628 (1997)

H.Niiro：“Interleukin-10 和 Interleukin-4 对人类中性粒细胞中环氧酶 2 表达的调节。”

K.Izuhara: "Regulation of STAT5 in lipopolysac charide-stimulated monocytes." Bullet.Cell Sci.Res.Found.8. 48-59 (1997)

K.Izuhara：“脂多糖刺激的单核细胞中 STAT5 的调节。”

Harada N: "Identification of the Critical Portions of the Human IL-4 Receptor α Chain for Activation of STATE." Biochem. Biophys. Res. Commun.246. 675-680 (1998)

Harada N：“生物化学研究中人 IL-4 受体 α 链的关键部分的鉴定”。 246。

Sugimoto R: "Cloning and Characterization of Hakata Antigen, a Member of the Ficolin/Opsonin P35 Lectin Family" J.Biol.Chem.273. 20721-20727 (1998)

Sugimoto R：“Ficolin/调理素 P35 凝集素家族成员博多抗原的克隆和表征”J.Biol.Chem.273。

Izuhara K: "The Signal Transluction via The Interleckin-4 Receptor and Its Correlation with Atopy" Int.J.Mol.Med.3. 3-10 (1999)

Izuhara K：“通过 Interleckin-4 受体的信号转导及其与特应性的相关性”Int.J.Mol.Med.3。