Abstract
Interleukin-12 (IL-12) and IL-18 induce synergistic transcription of interferon gamma (IFN-gamma) that is T cell receptor (TCR)-independent, not inhibited by cyclosporin A and requires new protein synthesis. To characterize this pathway, we screened for genes that are induced in IL-12- and IL-18-treated T helper type 1 cells. GADD45 beta, which activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12. GADD45 beta expression in naïve CD4+ T cells activated p38 MAPK and selectively increased cytokine-induced, but not TCR-induced, IFN-gamma production. Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both selectively inhibit cytokine-induced, but not TCR-induced, IFN-gamma production. Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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Cell Line
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Cytokines / pharmacology
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DNA Primers / genetics
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GADD45 Proteins
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Humans
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Interferon-gamma / biosynthesis*
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Interleukin-12 / pharmacology
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Interleukin-18 / pharmacology*
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase Kinase 4
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / metabolism
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Protein Biosynthesis
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Cytokines
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DNA Primers
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Interleukin-18
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Intracellular Signaling Peptides and Proteins
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Proteins
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Receptors, Antigen, T-Cell
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Interleukin-12
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Interferon-gamma
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 4
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MAP Kinase Kinase Kinases
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MAP3K4 protein, human
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Map3k4 protein, mouse