MD-2 as the Target of Nonlipid Chalcone in the Inhibition of Endotoxin LPS-Induced TLR4 Activity

• Published in: The Journal of infectious diseases 2011-04, Vol.203 (7), p.1012-1020
• Main Authors: Roh, Eunmiri, Lee, Heun-Sik, Kwak, Jeong-Ah, Hong, Jin Tae, Nam, Sang-Yoon, Jung, Sang-Hun, Lee, Joo Young, Kim, Nam Doo, Han, Sang-Bae, Kim, Youngsoo
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - immunology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antibodies; BACTERIA; Biological and medical sciences; Cell extracts; Cells, Cultured; Chalcone - pharmacology; Chalconoids; Endotoxins - immunology; Endotoxins - toxicity; Fluorescence; Fundamental and applied biological sciences. Psychology; Genes; Immunologic Factors - pharmacology; Infectious diseases; Lipids; Lipopolysaccharides; Lymphocyte Antigen 96; Macrophages; Macrophages - drug effects; Macrophages - immunology; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Microbiology; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; Nitric Oxide Synthase - antagonists & inhibitors; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - immunology; Transfection
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiq155

Myeloid differentiation 2 (MD-2) recognizes endotoxin lipopolysaccharide (LPS), which is required for Tolllike 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-(NF-ºB) activation that involves the phosphorylation and degradation of inhibitory ºBS and the nuclear import and transcriptional activity of NF-ºA in LPS-activated macrophages. Moreover, JSH suppressed NF-KB-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.