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

Abstract

Sepsis is a systemic inflammatory response resulting from the excessive production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α. 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-α. Chromatin immunoprecipitation and real-time PCR were used to determine the transcription of the TNF-α promoter. The result revealed that the binding of SirT1 to the TNF-α 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-α promoter. However, the activity of SirT1 was increased and binding of ace-H4K16 to the TNF-α 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-α 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.

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

“…On the other hand, previous reports indicate that nuclear sirtuins (SIRT1, SIRT2, and SIRT6) deacetylate H3 and H4 histones in chromatin in a gene-specific manner. 11,25,26 In the framework of gene expression, histone H3 acetylation at specific lysine residues (H3K56, H3K14, H3K9, and H3K27) is associated with actively transcribed genes, while deacetylation correlates with repression. For this reason, we examined the potential role of this epigenetic mechanism.…”

Biological Effects and Properties of Eukaryotic Sirtuins

“…При цьому вони ендоцитують, гідролізують та реете-рифікють ефіри холестерину, стаючи таким чином ксантомними клітинами. Останні внас-лідок дерегуляції їх ефероцитозу масово про-грамовано гинуть, формуючи ядро вторин-ного некрозу в атеросклеротичних бляшках, які, в свою чергу, закупорюють судини [23,50,51]. Визначено, що надлишкова експресія SIRT1 у ендотеліальних клітинах або при вве-денні мишам активатора SIRT1 ресвератролу, зменшує кількість активних форм кисню в Рис.3.…”

“…Амілоїди в клітинах людей, які страждають на хворобу Альцгеймера, підсилюють ацетилювання RELA-субодиниці в мікроглії мозку, акти-вуючи NF-κB. При цьому SIRT1 деацетилює NF-κB, захищаючи таким чином нейрони [15,38,51].…”

Absence of Sirtuin 1 impairs the testicular development in cattleyak by inactivating SF‐1

“…The function of SIRT1 is usually realized by deacetylating histone or non‐histone substrates. For example, SIRT1 can repress the expression of tumour necrosis factor (TNF)‐α via deacetylation the 16th lysine (K) of histone H4 (H4K16) (Chen, Yu, & Chen, 2016) and it also can inhibit cell apoptosis via deacetylating P53 at the 379th lysine (P53‐K379ac) (Gomes et al., 2016; Vaziri et al., 2001). In addition, SIRT1 can realize its function by directly interacting with other proteins.…”