Inhibitory mechanism of MMP-9 gene expression by ethyl pyruvate in lipopolysaccharide-stimulated BV2 microglial cells.

Abstract

Ethyl pyruvate (EP) is a stable derivative of pyruvate and has been identified as a therapeutic agent for various inflammatory diseases. In the present study, we showed that EP and sodium pyruvate (SP) inhibited the production of TNF-α, nitric oxide (NO), or reactive oxygen species (ROS) in LPS-stimulated BV2 microglial cells. The inhibitory effects of EP were more potent than SP. Because matrix metalloproteinase-9 (MMP-9) plays a key role in neuroinflammation, as well as in neuronal cell death, we examined the effect of EP on MMP-9 expression. RT-PCR and Western blot analyses revealed that EP inhibits MMP-9 expression at mRNA and protein levels in LPS-stimulated BV2 cells. In addition, EP suppressed MMP-9 secretion, as demonstrated by gelatin zymography analysis. In contrast, SP did not affect MMP-9 expression at an equivalent concentration of EP. Further mechanistic studies revealed that EP inhibits MMP-9 promoter activity by reducing the binding of NF-κB and AP-1 to its cognitive binding sites. In addition, EP suppressed LPS-induced phosphorylation of p38 MAPK, ERK, and Akt, which are upstream signaling molecules in MMP-9 gene expression. Taken together, our data suggest that the inhibition of MMP-9 may be one of the factors contributing to anti-inflammatory activity of EP in LPS-stimulated microglia.

• Authors: Eun-Jung Lee, Hee-Sun Kim
• Journal: Neuroscience letters (Neurosci Lett) Vol. 493 Issue 1-2 Pg. 38-43 (Apr 08 2011) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 21316417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Inflammation Mediators
• Lipopolysaccharides
• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors
• Pyruvates
• RNA, Messenger
• ethyl pyruvate
• Matrix Metalloproteinase 9

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Line, Transformed
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Inflammation Mediators (pharmacology)
• Lipopolysaccharides (pharmacology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Matrix Metalloproteinase Inhibitors
• Mice
• Microglia (drug effects, enzymology, pathology)
• Protease Inhibitors (pharmacology)
• Pyruvates (pharmacology)
• RNA, Messenger (antagonists & inhibitors, metabolism)