Sirtuin 1 is a key regulator of the IL-12 p70/IL-23 balance in human dendritic cells

Abstract

Stimulation of human dendritic cells (DC) 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 this has not been fully addressed. Zymosan induced the expression of SIRT1 in the nucleus, its association with the il12a promoter, increased the nuclear concentration of the SIRT1 cosubstrate NAD+, and decreased chromatin accessibility in the nucleosome 1 of il12a. Modulation of NAD+ nuclear levels by FK866 and phthalic acid reversed the inhibitory effect of zymosan on il12a expression. The involvement of deacetylation reactions in the inhibition of il12a transcription was supported by the absence of Ac-K14-histone H3 in DC 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-¿B family involved in il12a regulation. These data indicate that an enhancement of SIRT1 activity may reduce the accessibility of c-Rel to the il12a promoter and its transcriptional activation, thus regulating the IL-12 p70/IL-23 balance.