title: 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-κB pathway in BV2 microglial cells.
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 IκB and p65/RelA NF-κB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-κB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-κB target genes, such as those for COX-2, iNOS, and IL-1β, 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/IκB kinase (IKK)/NF-κB signaling pathway.
authors.affiliation: Department of Biomedical Science and Technology, Research Center for Transcription Control, SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul, Korea.
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jeon
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Changyoun
authors.initials: C
authors.lastname: Kim
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Koh
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Kyooseob
authors.initials: K
authors.lastname: Ha
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C576975:2-hydroxy-3',5,5'-trimethoxychalcone; D047188:Chalcones; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C498143:RELA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase