SirT1 activator represses the transcription of TNF-α 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.