Analysis of IL-18 signaling pathways accounting for its various biological actions

IL-18是在先天免疫激活时分泌的多效性细胞因子。与IL-12组合，IL-18诱导来自各种类型细胞（包括NK细胞、CD 4 + T细胞和树突状细胞）的Th 1相关细胞因子，例如IFN-g。与IL-2一起，IL-18使初始CD 4 + T细胞产生Th 2相关的细胞因子，如IL-4和IL-13。此外，IL-18加IL-3触发嗜碱性粒细胞和肥大细胞产生IL-4和IL-13以及组胺释放，而无需其FcεR交联。IL-18仅激活NK细胞，以产生IFN-γ并增强其NK活性。因此，IL-18似乎参与各种免疫病理学改变，如炎性疾病、高IgE综合征和过敏性疾病。在这里，我们研究了IL-18诱导的各种生物学事件的分子机制，特别是关注IL-1介导的信号通路，因为IL-1和IL-18之间的受体的胞内结构域的同源性。髓样分化因子88是IL-1信号传导所必需的细胞内信号接头，突变小鼠在IL-12存在下，经IL-18刺激后，NK细胞活化和IFN-γ产生受损。接下来，我们测试了tyk 2在IL-18信号通路中的可能参与，因为tyk 2被证明是上调T细胞和NK细胞上IL-18 R表达的IL-12所必需的。Tyk 2缺陷型NK细胞不产生IFN-γ或IL-13，或响应于IL-18而增加其针对NK敏感性靶细胞的细胞毒性。Tyk 2缺陷型CD 4 ^+ T细胞分别在IL-12加IL-18和IL-2加IL-18的作用下不产生IFN-γ或IL-4/IL-13。这些结果表明tyk 2对于这些IL-18作用是重要的，尽管tyk 2是JAK激酶家族的成员并且参与stat介导的信号传导，其被认为不参与IL-18信号通路。

IL-18 is a pleiotropic cytokine secreted upon activation of innate immunity. In combination with IL-12, IL-18 induces Th1-related cytokines such as IFN-g from various types of cells including NK cells, CD4+ T cells and dendritic cells. Together with IL-2, IL-18 renders naive CD4+ T cells to produce Th2-related cytokines, such as IL-4 and IL-13. Furthermore, IL-18 plus IL-3 triggers IL-4 and IL-13 production and histamine release by basophils and mast cells without cross-linkage of their FcεR. IL-18 solely activates NK cells, to produce IFN-γ and to augment their NK activity. Therefore, IL-18 appears to be involved in various immunopathological alterations such as inflammatory diseases, hyper IgE syndrome and allergic disorders. Here, we investigated the molecular mechanisms underlying IL-18-induced various biological events, particularly focusing on IL-1-medtated signal pathway because of homology of intracellular domain of receptors between IL-1 and IL-18. Mutant mice tacking myeloid differentiation factor 88, an intracellular signal adaptor essential for IL-1 signaling, showed impairment in activation of NK cells and IFN-γ production in the presence of IL-12 upon stimulation with IL-18. Next, we tested possible involvement of tyk2 in IL-18 signal pathways, because tyk2 was demonstrated to be required for IL-12 that up-regulates IL-18R expression on T cells and NK cells. Tyk2-deficient NK cells did not produce IFN-γ or IL-13, or increase in its cytotoxicity against NK-sensitive target cells in response to IL-18. Tyk2-deficient CD4^+ T cells did not produce IFN-γ or IL-4/IL-13 in response to IL-12 plus IL-18 and IL-2 plus IL-18, respectively. These results suggested that tyk2 is important for these IL-18 actions, although tyk2 is a member of JAK kinase family and involved in stat-mediated signalings, which is believed not to be involved in IL-18 signal pathways.