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INVESTIGATION OF IL-18-INDUCED IgE RESPONSE FOCUSING ON ITS MyD88-INDEPENDENCY AND IL-4-DEPENDENCY

IL-18 诱导的 IgE 反应的研究，重点关注其 MyD88 独立性和 IL-4 依赖性

基本信息

批准号：
13470074
负责人：
NAKANISHI Kenji
金额：
$ 9.02万
依托单位：
Hyogo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470074/
关键词：
IL-18 MyD88 IgE NKT cells IL-4 Signal transduction IL-12 IFN-γ Myd88KOマウス

项目摘要

IL-18 was originally discovered as an IFN-γ-inducing factor. However, later studies revealed its potential to induce T cells to produce Th2-related cytokines, when it acts on T cells without IL-12. In the presence of IL-2,IL-18 stimulates T cells to produce Th2-cytokines. In the presence of IL-3,IL-18 stimulates basophils/ mast cells to produce Th2-cytokines, chemokines and chemical mediators. Through these studies, we could assume that local over-production of IL-18 may have capacity to induce innate-type atopy. In 2001,we could reveal that caspase-1 transgenic mice, that over expressed IL-18 in their keratinocytes, develop AD without their exposure to allergen. Furthermore, we showed that Stat 6-depeleted Caspase-1 transgenic mice developed compaciable level of AD even though they displayed no IgE in their sera. In 2002,we studied how systemic injection of IL-18 induces IgE response in normal mice. We found that IL-18 stimulates NKT cells, that constitutively express IL-18R, to produce IL-4 and to express CD40L in vivo. We also found such IL-18-stimulated NKT cells in collaboration with conventional T cells induce B cells to produce IgE. Finally, in 2003,we demonstrated that Th1 cell-transferred mice develop airway inflammation and hyperresponsiveness in response to nasully administered Ag plus IL-18. Therfore IL-18 may become important phamacological target molecule for the development of effective drugs for allergic disorders.

IL-18最初被发现是一种IFN-γ诱导因子。然而，后来的研究表明，当它在没有IL-12的情况下作用于T细胞时，它有可能诱导T细胞产生Th 2相关细胞因子。在IL-2的存在下，IL-18刺激T细胞产生Th 2-细胞因子。在IL-3存在的情况下，IL-18刺激嗜碱性粒细胞/肥大细胞产生Th 2细胞因子、趋化因子和化学介质。通过这些研究，我们可以假设局部IL-18的过度产生可能具有诱导先天型特应性的能力。在2001年，我们可以揭示，caspase-1转基因小鼠，过度表达IL-18在他们的角质形成细胞，发展AD没有他们暴露于过敏原。此外，我们还发现，Stat 6-depeleted Caspase-1转基因小鼠即使在其血清中不显示IgE，也会发展出相容水平的AD。2002年，我们研究了全身注射IL-18如何诱导正常小鼠的IgE反应。我们发现IL-18刺激组成型表达IL-18 R的NKT细胞产生IL-4并在体内表达CD 40 L。我们还发现这种IL-18刺激的NKT细胞与常规T细胞协同诱导B细胞产生IgE。最后，在2003年，我们证明了Th 1细胞转移的小鼠对鼻内给药的Ag + IL-18产生气道炎症和高反应性。因此，IL-18可能成为开发治疗过敏性疾病药物的重要药理学靶分子。