title: Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia.
abstract: Ethyl pyruvate (EP) has been demonstrated to have an anti-inflammatory function. However, the molecular mechanisms underlying the anti-inflammatory action of EP are largely unknown. We here show that EP exerts its anti-inflammatory effect by inhibiting ROS-dependent STAT signaling through its antioxidant activity, like vitamin C or N-acetyl-L-cysteine. The inhibition of STAT1 and STAT3 by EP prevented their translocation to the nucleus and consequently inhibited expression of iNOS and COX-2 by inhibiting STAT1- and STAT3-mediated transcriptional activity, followed by changes in chromatin conformation via deacetylation of histones H3 and H4 in both gene promoters. EP also suppressed transcripts of other STAT-responsive inflammatory genes such as IL-1beta, IL-6, TNF-alpha, and MCP-1. We further found that the mechanism of inhibition of STAT1 and STAT3 by EP is due to inhibition of JAK2 through Rac1 inactivation and SOCS1 induction. These findings offer new therapeutic possibilities for EP based on a better understanding of the mechanism underlying the action of EP.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Yongon-dong 28, Chungno-gu, Seoul 110-799, Korea.
authors.forename: Hong Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Ik Hyun
authors.initials: IH
authors.lastname: Cho
authors.forename: Ja Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Yong Jae
authors.initials: YJ
authors.lastname: Shin
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.forename: Wang-Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Chung
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000187:drug effects*; D050794:STAT1 Transcription Factor / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D011773:Pyruvates; D017382:Reactive Oxygen Species; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C046522:ethyl pyruvate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2