Exp Mol Med.
2012 Jun;44(6):369-377.
A new synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), suppresses the Toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-kappaB pathway in BV2 microglial cells
- Affiliations
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- 1Department of Biomedical Science and Technology, Research Center for Transcription Control, SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul 143-701, Korea. shinsy@konkuk.ac.kr
- 2Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
- 3Department of Applied Chemistry, Dongduk Women's University, Seoul 136-714, Korea.
- 4Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701, Korea.
- 5Mood Disorders Clinic and Affective Neuroscience Laboratory, Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam 463-707, Korea. kyooha@snu.ac.kr
Abstract
- Microglial cells are the resident innate immune cells that sense pathogens and tissue injury in the central nervous system (CNS). Microglial activation is critical for neuroinflammatory responses. The synthetic compound 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139) is a novel chalcone-derived compound. In this study, we investigated the effects of DK-139 on Toll-like receptor 4 (TLR4)-mediated inflammatory responses in BV2 microglial cells. DK-139 inhibited lipopolysaccharide (LPS)-induced TLR4 activity, as determined using a cell-based assay. DK-139 blocked LPS-induced phosphorylation of IkappaB and p65/RelA NF-kappaB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-kappaB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-kappaB target genes, such as those for COX-2, iNOS, and IL-1beta, in LPS-stimulated BV2 microglial cells. Interestingly, DK-139 blocked LPS-induced Akt phosphorylation. Inhibition of Akt abrogated LPS-induced phosphorylation of p65/RelA, while overexpression of dominant-active p110CAAX enhanced p65/RelA phosphorylation as well as iNOS and COX2 expression. These results suggest that DK-139 exerts an anti-inflammatory effect on microglial cells by inhibiting the Akt/IkappaB kinase (IKK)/NF-kappaB signaling pathway.
Keyword
MeSH Terms
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Animals
Binding Sites
Cell Line
Chalcones/chemistry/*pharmacology
Cyclooxygenase 2/metabolism
I-kappa B Kinase/metabolism
Inflammation/*drug therapy
Interleukin-1beta/metabolism
Lipopolysaccharides/immunology
Microglia/*drug effects/immunology/metabolism
Molecular Dynamics Simulation
NF-kappa B/*antagonists & inhibitors
Nitric Oxide Synthase Type II/metabolism
Phosphorylation/drug effects
Protein Binding
Proto-Oncogene Proteins c-akt/*antagonists & inhibitors
Rats
Signal Transduction
Toll-Like Receptor 4/*antagonists & inhibitors/metabolism
Transcription Factor RelA/metabolism
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