Specific phospholipid oxidation products inhibit ligand activation of toll-like receptors 4 and 2.
OBJECTIVE
We have previously shown that phospholipid oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) inhibit lipopolysaccharide (LPS)-induced E-selectin expression and neutrophil binding in human aortic endothelial cells (HAECs). The current studies identify specific phospholipids that inhibit chemokine induction by Toll-like receptor-4 (TLR4) and -2 (TLR2) ligands inECs and macrophages.


RESULTS
Measurements of interleukin (IL)-8 and monocyte chemotactic protein-1 levels secreted from ox-PAPC- and LPS-cotreated ECs indicate that ox-PAPC inhibits activation of TLR4 by LPS. The effects of IL-1beta and tumor necrosis factor-alpha, which utilize the same intracellular signaling molecules, were not inhibited. Cell fractionation and immunofluorescence analyses demonstrate that LPS induces membrane translocation of the LPS receptor complex to a lipid raft/caveolar fraction in ECs. Ox-PAPC inhibits this translocation and alters caveolin-1 distribution. Supporting an important role for caveolae in LPS action, overexpression of caveolin-1 enhanced LPS-induced IL-8 synthesis. Ox-PAPC also inhibits the effect of TLR2 and TLR4 ligands in human macrophages.


CONCLUSIONS
These studies report a novel mechanism that involves alterations to lipid raft/caveolar processing, by which specific phospholipid oxidation products inhibit activation by TLR4 and TLR2 ligands. These studies have broader implications for the role of ox-PAPC as a regulator of specific lipid raft/caveolar function.
Walton
Kimberly A
KA
Department of Medicine, University of California, Los Angeles, CA 90095-1732, USA.
Cole
Amy L
AL
Yeh
Michael
M
Subbanagounder
Ganesamoorthy
G
Krutzik
Stephan R
SR
Modlin
Robert L
RL
Lucas
Robert M
RM
Nakai
Junko
J
Smart
Eric J
EJ
Vora
Deven K
DK
Berliner
Judith A
JA
D000818:Animals; D018955:CD36 Antigens / Q000502:physiology; D002417:Cattle; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D051242:Caveolin 1; D022461:Caveolins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D010713:Phosphatidylcholines / Q000494:pharmacology* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C468114:1-palmitoyl-2-arachidonyl-3-phosphorylcholine; C495540:CAV1 protein, human; D018955:CD36 Antigens; D051242:Caveolin 1; D022461:Caveolins; D018932:Chemokine CCL2; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010713:Phosphatidylcholines; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha