Myeloid differentiation 2 (MD-2) recognizes endotoxin lipopolysaccharide (LPS), which is required for Toll-like receptor 4 (TLR4) activity. MD-2 represents a more attractive therapeutic target than TLR4 for intervention in severe inflammatory disorders due to microbial infection. Here, we suggest MD-2 as a molecular target of nonlipid chalcone in the inhibition of LPS-induced cellular inflammation. A chalcone derivative, 2′,4-dihydroxy-6′- isopentyloxychalcone (JSH) competitively displaced LPS from MD-2, and was fitted into the ligand-binding site on the crystal structure of MD-2 under the most energetically favorable simulation. JSH nullified TLR4 activation mechanism and sequentially inhibited nuclear factor-κB (NF-κB) activation that involves the phosphorylation and degradation of inhibitory κBs and the nuclear import and transcriptional activity of NF-κB in LPS-activated macrophages. Moreover, JSH suppressed NF-κB-target inflammatory genes such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β (IL-1β) and IL-6. Taken together, this study assigns the chalcone structure as an LPS antagonist binding to MD-2 with therapeutic potential against inflammatory conditions. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
CITATION STYLE
Roh, E., Lee, H. S., Kwak, J. A., Hong, J. T., Nam, S. Y., Jung, S. H., … Kim, Y. (2011). MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity. Journal of Infectious Diseases, 203(7), 1012–1020. https://doi.org/10.1093/infdis/jiq155
Mendeley helps you to discover research relevant for your work.