Abstract
Stimulation of human dendritic cells with the fungal surrogate zymosan produces IL-23 and a low amount of IL-12 p70. Trans-repression of il12a transcription, which encodes IL-12 p35 chain, by proteins of the Notch family and lysine deacetylation reactions have been reported as the underlying mechanisms, but a number of questions remain to be addressed. Zymosan produced the location of sirtuin 1 (SIRT1) to the nucleus, enhanced its association with the il12a promoter, increased the nuclear concentration of the SIRT1 co-substrate NAD(+), and decreased chromatin accessibility in the nucleosome-1 of il12a, which contains a κB-site. The involvement of deacetylation reactions in the inhibition of il12a transcription was supported by the absence of Ac-Lys-14-histone H3 in dendritic cells treated with zymosan upon coimmunoprecipitation of transducin-like enhancer of split. In contrast, we did not obtain evidence of a possible effect of SIRT1 through the deacetylation of c-Rel, the central element of the NF-κB family involved in il12a regulation. These data indicate that an enhancement of SIRT1 activity in response to phagocytic stimuli may reduce the accessibility of c-Rel to the il12a promoter and its transcriptional activation, thus regulating the IL-12 p70/IL-23 balance and modulating the ongoing immune response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Cell Nucleus / genetics
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Cell Nucleus / immunology
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Cell Nucleus / metabolism*
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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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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Histones / genetics
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Histones / immunology
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Histones / metabolism
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Humans
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Interleukin-12 Subunit p35 / biosynthesis*
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Interleukin-12 Subunit p35 / genetics
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Interleukin-12 Subunit p35 / immunology
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Interleukin-23 / genetics
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Interleukin-23 / immunology
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Interleukin-23 / metabolism*
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Mice
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Mice, Mutant Strains
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic / physiology
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Proto-Oncogene Proteins c-rel
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Receptors, Notch / genetics
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Receptors, Notch / immunology
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Receptors, Notch / metabolism
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Sirtuin 1 / genetics
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Sirtuin 1 / immunology
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Sirtuin 1 / metabolism*
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Transcription Factor RelA / genetics
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Transcription Factor RelA / immunology
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Transcription Factor RelA / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Transcription, Genetic / immunology
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Zymosan / pharmacology
Substances
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DNA-Binding Proteins
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Histones
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IL12A protein, human
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Interleukin-12 Subunit p35
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Interleukin-23
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Nuclear Proteins
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Proto-Oncogene Proteins c-rel
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REL protein, human
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RELA protein, human
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Receptors, Notch
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Transcription Factor RelA
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Zymosan
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SIRT1 protein, human
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Sirtuin 1