Abstract
PMA and ionomycin cause T cell cytokine production. We report that ionomycin alone induces IL-4 and IFN-gamma, but not IL-2, from in vivo- and in vitro-generated murine Th2 and Th1 cells. Ionomycin-induced cytokine production requires NFAT, p38, and calmodulin-dependent kinase IV (CaMKIV). Ionomycin induces p38 phosphorylation through a calcium-dependent, cyclosporine A-inhibitable pathway. Knocking down ASK1 inhibits ionomycin-induced p38 phosphorylation and IL-4 production. Ionomycin also activates CaMKIV, which, together with p38, induces AP-1. Cooperation between AP-1 and NFAT leads to Il4 gene transcription. p38 also regulates IL-4 production by mRNA stabilization. TCR stimulation also phosphorylates p38, partially through the calcium-dependent pathway; activated p38 is required for optimal IL-4 and IFN-gamma.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Calcium Signaling / drug effects
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Calcium Signaling / genetics
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Calcium Signaling / immunology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Interferon-gamma / biosynthesis
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics*
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Interleukin-4 / metabolism*
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Ionomycin / pharmacology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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RNA Stability / immunology*
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RNA, Messenger / metabolism*
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Schistosomiasis mansoni / immunology
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Schistosomiasis mansoni / metabolism
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Schistosomiasis mansoni / pathology
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Th2 Cells / parasitology
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Transcription, Genetic*
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Up-Regulation / immunology*
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p38 Mitogen-Activated Protein Kinases / metabolism
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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RNA, Messenger
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Interleukin-4
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Ionomycin
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Interferon-gamma
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p38 Mitogen-Activated Protein Kinases