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Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia

Cited 70 time in Web of Science Cited 69 time in Scopus
Authors
Kim, Hong Sook; Cho, Ik Hyun; Kim, Ja Eun; Shin, Yong Jae; Jeon, Ju-Hong; Kim, Youngsoo; Yang, Young Mok; Lee, Kwang-Ho; Lee, Jung Weon; Lee, Wang-Jae; Ye, Sang-Kyu; Chung, Myung-Hee
Issue Date
2008-07-16
Publisher
Elsevier
Citation
Free Radic Biol Med. 45(7):950-63
Keywords
AnimalsAnti-Inflammatory Agents/*pharmacologyCell LineCyclooxygenase 2/biosynthesis/drug effectsFluorescent Antibody TechniqueGene Expression/drug effectsMaleMiceMice, Inbred C57BLMicroglia/*drug effects/metabolismProtein Transport/drug effectsPyruvates/*pharmacologyReactive Oxygen Species/*metabolismReverse Transcriptase Polymerase Chain ReactionSTAT Transcription Factors/*drug effectsSTAT1 Transcription Factor/drug effectsSTAT3 Transcription Factor/drug effectsSignal Transduction/*drug effectsTranscription, Genetic/drug effects
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.
ISSN
0891-5849 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18625301

http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T38-4SS6VPC-1-10&_cdi=4940&_user=168665&_orig=search&_coverDate=10%2F01%2F2008&_sk=999549992&view=c&wchp=dGLzVlz-zSkzS&md5=94144e18f6001af33855293d50398876&ie=/sdarticle.pdf

http://hdl.handle.net/10371/68137
DOI
https://doi.org/10.1016/j.freeradbiomed.2008.06.009
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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