Multi-hit inhibition of circulating and cell-associated components of the toll-like receptor 4 pathway by oxidized phospholipids.
OBJECTIVE
Oxidized phospholipids (OxPLs) that are abundant in atherosclerotic lesions are increasingly recognized as context-dependent lipid mediators demonstrating both pro- and antiinflammatory activities. Molecular mechanisms of their effects are largely unknown. Here we present novel information on the mechanisms whereby OxPLs modulate activation of TLR4 by lipopolysaccharide (LPS).


RESULTS
We show, using several cell types and various inflammatory genes as readouts, that different classes and molecular species of OxPLs do not stimulate TLR4 but exert prominent inhibitory effects on LPS-induced reactions. Our data demonstrate that binding of OxPLs to the LPS-binding protein (LBP) and CD14 prevents recognition of LPS by these proteins, thus impairing activation of TLR4. In addition, OxPLs inhibited LBP- and CD14-independent activation of TLR4 by the synthetic TLR4 agonist E6020 indicating that in parallel with LBP and CD14, OxPLs target cell-associated steps in TLR4 cascade.


CONCLUSIONS
Our data suggest that OxPLs inhibit action of LPS via a multi-hit mechanism. These results support the notion that OxPLs are endogenous inhibitors of TLR4 produced in response to oxidative stress.
von Schlieffen
Elena
E
Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.
Oskolkova
Olga V
OV
Schabbauer
Gernot
G
Gruber
Florian
F
Blüml
Stephan
S
Genest
Melinda
M
Kadl
Alexandra
A
Marsik
Claudia
C
Knapp
Sylvia
S
Chow
Jesse
J
Leitinger
Norbert
N
Binder
Bernd R
BR
Bochkov
Valery N
VN
D000209:Acute-Phase Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007700:Kinetics; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D019040:E-Selectin; D018836:Inflammation Mediators; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010743:Phospholipids; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein; C508600:IL6 protein, human; C495345:TLR4 protein, human