S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia
- 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
- Free Radic Biol Med. 45(7):950-63
- Animals; Anti-Inflammatory Agents/*pharmacology; Cell Line; Cyclooxygenase 2/biosynthesis/drug effects; Fluorescent Antibody Technique; Gene Expression/drug effects; Male; Mice; Mice, Inbred C57BL; Microglia/*drug effects/metabolism; Protein Transport/drug effects; Pyruvates/*pharmacology; Reactive Oxygen Species/*metabolism; Reverse Transcriptase Polymerase Chain Reaction; STAT Transcription Factors/*drug effects; STAT1 Transcription Factor/drug effects; STAT3 Transcription Factor/drug effects; Signal Transduction/*drug effects; Transcription, Genetic/drug effects
- 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.
- 0891-5849 (Print)
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