Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-gamma production by dendritic cells.
Mouse splenic dendritic cells (DCs) produce IFN-gamma in response to IL-12. In the present study, we analyzed effects of Th1 and Th2 cytokines on IFN-gamma production by DCs. IL-18 produced by DCs and macrophages acts in an autocrine manner and augments IL-12-induced IFN-gamma production by DCs as also observed in T and NK cells. Surprisingly, IL-4, a Th2 cytokine, also acts synergistically with IL-12 on IFN-gamma production by DCs. In addition, IL-4 markedly enhances IFN-gamma production when DCs are stimulated through CD40 or MHC class II. These results indicate that both Th1 and Th2 cytokines act on DCs during T cell-DC interaction upon Ag presentation. p38 mitogen-activated protein kinase is constitutively activated in mature DCs and is required for IFN-gamma production by DCs. IL-18 but not IL-4 or IL-12 further activates the p38 mitogen-activated protein kinase activity, suggesting that IL-4 and IL-18 enhance IFN-gamma production through distinct intracellular signal transduction pathways in DCs.
Fukao
T
T
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Matsuda
S
S
Koyasu
S
S
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology; D016827:CD8 Antigens / Q000096:biosynthesis; D003713:Dendritic Cells / Q000145:classification / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; D020382:Interleukin-18; D007378:Interleukins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases