[Regulation of Th1 and Th2 immune responses by IL-18].
IL-18, which requires cleavage with caspase-1 to become active, was originally discovered as a factor that enhances IFN-gamma production from Th1 cells in the presence of anti-CD3 or anti-TcR Ab. However, it was later shown that IL-12 and IL-18 without TcR engagement can induce IFN-gamma in Th1 cells and nonpolarized T cells. Additional TcR engagement has no effect on this IFN-gamma response. Furthermore, a combination of IL-12 and IL-18 acts on B cells, NK cells, macrophages and dendritic cells to produce IFN-gamma. In contrast, IL-18 without help from IL-12 induces Th2 cytokines in T cells and NK cells. Moreover, IL-18 directly stimulates basophils and mast cells to produce Th2 cytokines and histamine independently of IgE. Most surprisingly, IL-18 causes high-level IgE production when administered to normal mice by causing CD4+ T cells to produce IL-4 and to express CD 40 ligand. We established skin-specific caspase-1 transgenic mice with elevated levels of IL-18 in their sera. We found high serum level of IgE, which is entirely dependent on stat 6 in these transgenic mice. These results indicate that caspase-1/IL-18 may be critically involved in regulation of IgE production in vivo, providing a potential therapeutic target for allergic disorders.
Nakanishi
Kenji
K
Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya-shi, Hyogo 663-8501, Japan.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D020170:Caspase 1 / Q000502:physiology; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007073:Immunoglobulin E / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic / Q000502:physiology; D018123:Receptors, Interleukin / Q000502:physiology; D053724:Receptors, Interleukin-18; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D007073:Immunoglobulin E; D020170:Caspase 1