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IFN-γ诱导的因子。然而，后来的研究表明，当它作用于无IL-12的T细胞上时，其可能诱导T细胞产生与Th2相关的细胞因子的潜力。在存在IL-2的情况下，IL-18刺激T细胞产生Th2-促动力学。在存在IL-3的情况下，IL-18刺激嗜碱性粒细胞/肥大细胞产生Th2-循环因子，趋化因子和化学介质。通过这些研究，我们可以假设IL-18的局部生产过量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，即在其角质形成细胞中表达IL-18的caspase-1转基因小鼠，而无需暴露于过敏原而发展AD。此外，我们证明了STAT 6用骨骼的caspase-1转基因小鼠在血清中没有显示IgE，而它们也没有表现出可兼容的AD水平。在2002年，我们研究了IL-18的全身注射如何在正常小鼠中诱导IgE反应。我们发现IL-18刺激组成型表达IL-18R的NKT细胞产生IL-4并在体内表达CD40L。我们还发现这种IL-18刺激的NKT细胞与常规T细胞合作诱导B细胞产生IgE。最后，在2003年，我们证明了Th1细胞转移的小鼠会响应于纳苏尔施用的Ag Plus IL-18而产生气道注射和过度反应性。因此，IL-18可能会成为为过敏性疾病开发有效药物的重要手术靶标分子。