title: Ethyl pyruvate inhibits the acetylation and release of HMGB1 via effects on SIRT1/STAT signaling in LPS-activated RAW264.7 cells and peritoneal macrophages.
abstract: High mobility group box 1 (HMGB1), a cytokine present in the late phase of sepsis, may be a potential target for the treatment of sepsis. For HMGB1 to be actively secreted from macrophages during infections, it must be post-translationally modified. Although ethyl pyruvate (EP), a simple aliphatic ester derived from pyruvic acid, has been shown to inhibit the release of HMGB1 in lipopolysaccharide (LPS)-treated RAW 264.7 cells, the underlying mechanism(s) are not yet clear. We investigated the hypothesis that the upregulation of SIRT1 by EP might promote the deacetylation of HMGB1, which reduces HMGB1 release in LPS-activated macrophages. Our results show that EP induced the expression of the SIRT1 protein in RAW264.7 cells and that it significantly inhibited the LPS-induced acetylation of HMGB1. Transfection with a SIRT1-overexpressing vector resulted in a significant decrease in the acetylation of HMGB1 in LPS-activated RAW264.7 cells relative to control cells. The genetic ablation or the pharmacological inhibition of SIRT1 by sirtinol increased LPS-induced HMGB1 acetylation. Moreover, EP inhibited the acetylation of HMGB1 in peritoneal macrophages treated with LPS. Interestingly, EP significantly reduced the LPS-induced phosphorylation of STAT1, which was significantly reversed by siSIRT1 transfection in RAW264.7 cells, indicating that SIRT1 negatively regulates the phosphorylation of STAT1. Overall, the results show that EP promotes the deacetylation of HMGB1 via the inhibition of STAT1 phosphorylation through the upregulation of SIRT1, which reduces HMGB1 release in LPS-activated RAW264.7 cells. In conclusion, EP might be useful in the treatment of diseases that target HMGB1, such as sepsis.
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Republic of Korea; Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 660-751, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D011773:Pyruvates; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C046522:ethyl pyruvate; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Ethyl pyruvate; HMGB1; Inflammation; SIRT1; STAT signal; Sepsis