MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity

Eunmiri Roh, Heun Sik Lee, Jeong Ah Kwak, Jin Tae Hong, Sang Yoon Nam, Sang Hun Jung, Joo Young Lee, Nam Doo Kim, Sang Bae Han, Youngsoo Kim

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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.

Original languageEnglish (US)
Pages (from-to)1012-1020
Number of pages9
JournalJournal of Infectious Diseases
Issue number7
StatePublished - Apr 1 2011

Bibliographical note

Funding Information:
This work was supported by Priority Research Center grant 2009– 0094035 and Medical Research Center grant R13-2008-001-0000-00 from the National Research Foundation of Korea, and a research fund from Chungbuk BIT Research-Oriented University Consortium.

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