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
  • 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

chalcone; lipopolysaccharides; microglia; NF-kappaB; proto-oncogene proteins c-akt; Toll-like receptor 4
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