Inhibition of LPS- and CpG DNA-induced TNF-alpha response by oxidized phospholipids.
Lipid oxidation is commonly seen in the innate immune response, in which reactive oxygen intermediates are generated to kill pathogenic microorganisms. Although oxidation products of phospholipids have generally been regarded to play a role in a number of chronic inflammatory processes, several studies have shown that oxidized phospholipids inhibit the LPS-induced acute proinflammatory response in cultured macrophages and endothelial cells. We report in this study that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), but not nonoxidized PAPC, significantly inhibits the LPS-induced TNF-alpha response in intact mice. Oxidized PAPC also inhibits the 2'-deoxyribo(cytidine-phosphate-guanosine) (CpG) DNA-induced TNF-alpha response in cultured macrophages and intact mice. To elucidate the mechanisms of action, we show that oxidized PAPC, but not nonoxidized PAPC, inhibits the LPS- and CpG-induced activation of p38 MAPK and the NF-kappaB cascade. These results suggest a role for oxidized lipids as a negative regulator in controlling the magnitude of the innate immune response. Further studies on the mechanisms of action may lead to development of a new type of anti-inflammatory drug for treatment of acute inflammatory diseases such as sepsis.
Ma
Zheng
Z
Center for Pharmacogenetics, Univ. of Pittsburgh School of Pharmacy, 639 Salk Hall, Pittsburgh, PA 15213, USA.
Li
Jiang
J
Yang
Lijuan
L
Mu
Ying
Y
Xie
Wen
W
Pitt
Bruce
B
Li
Song
S
D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
C468114:1-palmitoyl-2-arachidonyl-3-phosphorylcholine; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases