title: MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity.
abstract: 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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Korea.
authors.forename: Eunmiri
authors.initials: E
authors.lastname: Roh
authors.forename: Heun-Sik
authors.initials: HS
authors.lastname: Lee
authors.forename: Jeong-Ah
authors.initials: JA
authors.lastname: Kwak
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Nam
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Jung
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002599:Chalcone / Q000494:pharmacology*; D004731:Endotoxins / Q000276:immunology* / Q000633:toxicity*; D007155:Immunologic Factors / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004731:Endotoxins; D007155:Immunologic Factors; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002599:Chalcone; D019001:Nitric Oxide Synthase