SirT1 activator represses the transcription of TNF-alpha in THP-1 cells of a sepsis model via deacetylation of H4K16

Sepsis is a systemic inflammatory response resulting from the excessive production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. Sirtuin 1 (SirT1) actively deacetylates histone proteins, and facilitates chromatin compaction and gene silencing. In the present study, a cell model of sepsis, comprising lipopolysaccharide (LPS)-tolerant THP-1 cells, was used to investigate whether the SirT1 activator, resveratrol, repressed the transcription of TNF-alpha. Chromatin immunoprecipitation and real-time PCR were used to determine the transcription of the TNF-alpha promoter. The result revealed that the binding of SirT1 to the TNF-alpha promoter was decreased by LPS stimulation in normal cells. However, in LPS-tolerant cells, nuclear protein levels of SirT1 remained elevated, and LPS stimulation had no significant effect on the binding of SirT1 to the TNF-alpha promoter. However, the activity of SirT1 was increased and binding of ace-H4K16 to the TNF-alpha promoter was decreased with resveratrol treatment in the tolerant cells. It was concluded that resveratrol stimulated sirtuin activity in LPS-tolerant THP-1 cells, and repressed TNF-alpha transcription through the deacetylation of H4K16, without affecting the methylation of H3K9. Resveratrol offers potential as an infective candidate to alleviate inflammation in patients with sepsis.National Natural Science Foundation of China [81201250]; National Key Technology Support Program [2012BAI11B05]SCI(E)ARTICLEchenxiaoping@icdc.cn65544-55501