Dilinoleoylphosphatidylcholine decreases LPS-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats: respective roles of MAPKs and NF-kappaB.
Activation of Kupffer cells by lipopolysaccharide (LPS) after ethanol feeding results in overproduction of TNF-alpha, leading to liver injury. Since dilinoleoylphosphatidylcholine (DLPC) protects against liver injury and has antioxidant properties, we investigated whether it alters LPS signaling leading to decreased TNF-alpha production. Kupffer cells were isolated from rats fed alcohol-containing or isocaloric control diets for 3 weeks. With ethanol, cytochrome P4502E1 was upregulated. When stimulated with LPS in culture, Kupffer cells released more TNF-alpha compared to control rats; DLPC diminished the increase. It also reduced ERK1/2 and p38 phosphorylation as well as NF-kappaB activation with decreased nuclear p65 and increased cytosolic IkappaB-alpha expression. ERK1/2 and NF-kappaB activation were abolished by the ERK1/2 inhibitor PD098059. The p38 inhibitor SB203580 abolished p38 activation without affecting NF-kappaB. Both inhibitors reduced TNF-alpha generation. Thus, DLPC diminishes LPS-dependent TNF-alpha generation by inhibiting p38 and ERK1/2 activation; the latter leads to decreased NF-kappaB activation.
Cao
Qi
Q
Alcohol Research and Treatment Center, Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, NY 10468, USA.
Mak
Ki M
KM
Lieber
Charles S
CS
D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D020672:I-kappa B Proteins; D015151:Immunoblotting; D007728:Kupffer Cells / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D010713:Phosphatidylcholines; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000431:Ethanol; C002448:1,2-linoleoylphosphatidylcholine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one