title: 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.
authors.affiliation: Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, P.R. China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Chen
authors.affiliation: Central Laboratory, Peking University People's Hospital, Beijing 100044.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Yu
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Nosocomial Infection, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, P.R. China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D002460:Cell Line; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D006657:Histones; D012333:RNA, Messenger; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D056564:Sirtuin 1; D000077185:Resveratrol