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

IL-18最初是作为IFN-γ诱导因子被发现的。然而，后来的研究表明，当它作用于没有IL-12的T细胞时，它有可能诱导T细胞产生th2相关的细胞因子。在IL-2存在的情况下，IL-18刺激T细胞产生th2细胞因子。在IL-3存在的情况下，IL-18刺激嗜碱性细胞/肥大细胞产生th2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IL-18的局部过量产生可能具有诱导先天型特应性的能力。在2001年，我们发现caspase-1转基因小鼠，在其角质形成细胞中过度表达IL-18，在没有暴露于过敏原的情况下发生AD。此外，我们发现Stat - 6缺失的Caspase-1转基因小鼠即使在血清中不显示IgE，也会发展出稳定水平的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刺激组成性表达IL-18R的NKT细胞在体内产生IL-4并表达CD40L。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Th1细胞转移的小鼠对鼻腔给药Ag + IL-18产生气道炎症和高反应性。因此，IL-18可能成为开发过敏性疾病有效药物的重要药理学靶点分子。

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.