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

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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.