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.
- Author:
Young Han LEE
1
;
Seung Hyun JEON
;
Se Hyun KIM
;
Changyoun KIM
;
Seung Jae LEE
;
Dongsoo KOH
;
Yoongho LIM
;
Kyooseob HA
;
Soon Young SHIN
Author Information
1. Department 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
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
chalcone;
lipopolysaccharides;
microglia;
NF-kappaB;
proto-oncogene proteins c-akt;
Toll-like receptor 4
- MeSH:
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
- From:Experimental & Molecular Medicine
2012;44(6):369-377
- CountryRepublic of Korea
- Language:English
-
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.
