Sirtuin 1 Is a Key Regulator of the Interleukin-12 p70/Interleukin-23 Balance in Human Dendritic Cells

Yolanda Alvarez,Mario Rodríguez,Cristina Municio,Etzel Hugo,Sara Alonso,Nieves Ibarrola,Nieves Fernández,Mariano Sánchez Crespo

doi:10.1074/jbc.m112.391839

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.

Highlights

Notch family transcriptional repressors explain the predominant production of IL-23 elicited by ␤-glucans
sirtuin 1 (SIRT1) and IL-12 p70 Production—Based on our previous findings suggesting that the sirtuin inhibitor EX-527 diminished the inhibitory effect of zymosan on the production of IL-12 p70 elicited by the combination of LPS and IFN␥, we tested whether activation of sirtuin activity with SRT1720 influenced IL-12 p70 in an opposite way
transducin-like enhancer of split (TLE), which has been found in the nucleus after zymosan treatment [12], was detected in the il12a promoter in control dendritic cells (DC) and after zymosan stimulation (Fig. 2D), suggesting that transcriptional repressors that directly or indirectly bind SIRT1 could be operative during SIRT1 induction

Summary

Background

Notch family transcriptional repressors explain the predominant production of IL-23 elicited by ␤-glucans. 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 in response to phagocytic stimuli may reduce the accessibility of c-Rel to the il12a promoter and its transcriptional activation, regulating the IL-12 p70/IL-23 balance and modulating the ongoing immune response. Zymosan modulates the acetylation of lysines in histones, thereby modifying the accessibility of transcription factors to the il12a promoter [12] This molecular mechanism is of clinical relevance because inhibition with the synthetic acetyl-histone mimic i-BET of interactions between acetylated histones and the bromodomains of proteins involved in transcriptional activation is a promising therapy in bacteria-induced sepsis. After having analyzed acetylation/deacetylation reactions of NF-␬B and histone proteins, we propose that the inhibition of il12a transcription elicited by zymosan is best explained by an increase of SIRT1 activity linked to an enhanced expression of the protein, an increased disposal of its co-substrate NADϩ, and the ensuing deacetylation of histones

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION