Inhibition of LPS- and CpG DNA-induced TNF-α 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.