title: Suppression of Toll-like receptor 4 activation by endogenous oxidized phosphatidylcholine, KOdiA-PC by inhibiting LPS binding to MD2.
abstract: OBJECTIVE
  Activation of Toll-like receptor 4 (TLR4) triggers immune and inflammatory events by sensing endogenous danger signals as well as invading pathogens and contributes to the development of chronic inflammatory diseases. In this study, we investigated effect of 1-palmitoyl-2-(5-keto-6-octenedioyl)-sn-glycero-3-phosphocholine (KOdiA-PC), an oxidized phosphatidylcholine, on TLR4 activation and the underlying regulatory mechanism.
  
  
  METHODS
  RAW264.7 macrophages were used for the study. The levels of TNF-α, IFN-β, and COX-2 mRNA and protein were determined by quantitative PCR and ELISA, respectively. Activation of TLR4-signaling was examined by immunoblot and luciferase reporter assays. In vitro binding assay was performed to determine LPS binding to MD2. Macrophage migration was analyzed using a transwell-culture system.
  
  
  RESULTS
  KOdiA-PC prevented the activation of TLR4-signaling components including ERK, JNK, p38, NF-κB, and IRF3 leading to decrease of TNF-α, IFN-β, and COX-2 expression. In vitro binding assay revealed that KOdiA-PC interrupted LPS binding to MD2, a TLR4 co-receptor. Consistently, KOdiA-PC suppressed LPS-induced macrophage migration.
  
  
  CONCLUSIONS
  The results demonstrate that KOdiA-PC can modulate TLR4 activation by regulating ligand-receptor interaction. Therefore, endogenously generated, oxidized phospholipids may play a role in resolving inflammation by terminating TLR activation and macrophage recruitment to the inflamed site.
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea.
authors.forename: Min Jin
authors.initials: MJ
authors.lastname: Kim
authors.forename: Na Young
authors.initials: NY
authors.lastname: Choi
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Koo
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sun Myung
authors.initials: SM
authors.lastname: Joung
authors.forename: Eunshil
authors.initials: E
authors.lastname: Jeong
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000276:immunology*; D051379:Mice; D010713:Phosphatidylcholines / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: C544327:1-palmitoyl-2-(5-keto-6-octenedioyl)phosphatidylcholine; D008024:Ligands; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D010713:Phosphatidylcholines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4