Ozonized low density lipoprotein (ozLDL) inhibits NF-kappaB and IRAK-1-associated signaling.
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.
Cappello
Christian
C
Institute of Clinical Chemistry and Pathobiochemistry, Technische Universität München, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 München, Germany.
Saugel
Bernd
B
Huth
Karin C
KC
Zwergal
Andreas
A
Krautkrämer
Martina
M
Furman
Christophe
C
Rouis
Mustapha
M
Wieser
Bianca
B
Schneider
Heike W
HW
Neumeier
Dieter
D
Brand
Korbinian
K
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
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D010126:Ozone; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases