title: Ozonized low density lipoprotein (ozLDL) inhibits NF-kappaB and IRAK-1-associated signaling.
abstract: OBJECTIVE
  Recent studies have provided strong evidence for the presence of ozone in atherosclerotic lesions. In addition, modification of LDL has been suggested to be involved in atherosclerosis. In the present study we wanted to investigate whether LDL exposed to ozone (ozLDL) is able to modulate the NF-kappaB system, as a paradigm for inflammatory signaling.
  
  
  RESULTS
  We showed that activation of NF-kappaB by lipopolysaccharide (LPS), a prototypic inducer of innate immunity, was reversibly inhibited by ozLDL in monocytic THP-1 cells in a dose-dependent manner, whereas tumor necrosis factor (TNF) signaling was not affected. This was not attributable to a direct ozone effect or solely the presence of lipoprotein, and neither required direct contact to LPS nor was accompanied by a change in LPS binding. Comparable inhibitory effects of ozLDL were observed in human monocyte/macrophages and endothelial cells. The presence of ozLDL led to a decrease in LPS-induced IkappaB alpha proteolysis and a reduction of kappaB-dependent transcription/target-gene expression. Furthermore, ozLDL markedly lowered stimulus-induced IkappaB kinase (IKK) activity and phosphorylation/proteolysis of interleukin (IL)-1 receptor-associated kinase-1 (IRAK-1). Finally, cholesterol ozonization products were identified as effective ozLDL inhibitory compounds.
  
  
  CONCLUSIONS
  Our study demonstrated that ozLDL inhibited NF-kappaB and IRAK-1-associated signaling which may impair immune function and promote apoptosis.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cappello
authors.forename: Bernd
authors.initials: B
authors.lastname: Saugel
authors.forename: Karin C
authors.initials: KC
authors.lastname: Huth
authors.forename: Andreas
authors.initials: A
authors.lastname: Zwergal
authors.forename: Martina
authors.initials: M
authors.lastname: Krautkrämer
authors.forename: Christophe
authors.initials: C
authors.lastname: Furman
authors.forename: Mustapha
authors.initials: M
authors.lastname: Rouis
authors.forename: Bianca
authors.initials: B
authors.lastname: Wieser
authors.forename: Heike W
authors.initials: HW
authors.lastname: Schneider
authors.forename: Dieter
authors.initials: D
authors.lastname: Neumeier
authors.forename: Korbinian
authors.initials: K
authors.lastname: Brand
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D010126:Ozone / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D010126:Ozone; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases