Sirtuin 1 is a key regulator of the interleukin-12 p70/interleukin-23 balance in human dendritic cells.
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.
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
Yolanda
Y
Alvarez
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
Mario
M
Rodríguez
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
Cristina
C
Municio
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
Etzel
E
Hugo
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain.
Sara
S
Alonso
Instituto de Biología Molecular y Celular del Cáncer, 37007 Salamanca, Spain.
Nieves
N
Ibarrola
Departamento de Bioquímica y Biología Molecular, y Fisiología, Universidad de Valladolid, 47005 Valladolid, Spain.
Nieves
N
Fernández
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, 47003 Valladolid, Spain. Electronic address: mscres@ibgm.uva.es.
Mariano Sánchez
MS
Crespo
D000107:Acetylation / Q000187:drug effects; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D020569:Proto-Oncogene Proteins c-rel; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015054:Zymosan / Q000494:pharmacology
D004268:DNA-Binding Proteins; D006657:Histones; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D053759:Interleukin-23; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; C498143:RELA protein, human; D051880:Receptors, Notch; D051996:Transcription Factor RelA; D015054:Zymosan; C447939:SIRT1 protein, human; D056564:Sirtuin 1