Abstract
Autocrine activation of APC by IL-12 has recently been revealed; we demonstrate here that inducible expression of Stat4 in APC is central to this process. Stat4 is induced in dendritic cells (DC) in a maturation-dependent manner and in macrophages in an activation-dependent manner. Stat4 levels directly correlate with IL-12-dependent IFN-gamma production by APC as well as IFN-gamma production by DC during Ag presentation. The Th2 cytokines IL-4 and IL-10 suppress Stat4 induction in DC and macrophages when present during maturation and activation, respectively, diminishing IFN-gamma production. In contrast, IL-4 has no effect on Stat4 levels in mature DC and actually augments IFN-gamma production by DC during Ag presentation, indicating that IL-4 acts differently in a spatiotemporal manner. The functional importance of Stat4 is evident in Stat4(-/-) DC and macrophages, which fail to produce IFN-gamma. Furthermore, Stat4(-/-) macrophages are defective in NO production in response to IL-12 and are susceptible to TOXOPLASMA: Autocrine IL-12 signaling is required for high-level IFN-gamma production by APC at critical stages in both innate and adaptive immunity, and the control of Stat4 expression is likely an important regulator of this process.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Autocrine Communication / genetics
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Autocrine Communication / immunology
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CD8 Antigens / biosynthesis
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cells, Cultured
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Cytokines / physiology
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism*
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Immunity, Cellular / genetics
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Immunity, Innate / genetics
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Injections, Intravenous
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Interferon-gamma / biosynthesis
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Interleukin-12 / physiology
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Lipopolysaccharides / administration & dosage
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Macrophage Activation / genetics
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / parasitology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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STAT4 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Toxoplasma / immunology
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Toxoplasma / pathogenicity
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Trans-Activators / biosynthesis*
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Up-Regulation / genetics
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Up-Regulation / immunology
Substances
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CD8 Antigens
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Cytokines
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DNA-Binding Proteins
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Lipopolysaccharides
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STAT4 Transcription Factor
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Stat4 protein, mouse
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Trans-Activators
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Interleukin-12
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Interferon-gamma