Cao Qi, Mak Ki M, Lieber Charles S
Alcohol Research and Treatment Center, Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, NY 10468, USA.
Biochem Biophys Res Commun. 2002 Jun 21;294(4):849-53. doi: 10.1016/S0006-291X(02)00586-7.
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.
乙醇喂养后，脂多糖（LPS）激活库普弗细胞会导致肿瘤坏死因子-α（TNF-α）过度产生，进而引发肝损伤。由于二亚油酰磷脂酰胆碱（DLPC）可预防肝损伤且具有抗氧化特性，我们研究了其是否会改变导致TNF-α产生减少的LPS信号传导。从喂食含酒精或等热量对照饮食3周的大鼠中分离出库普弗细胞。乙醇会使细胞色素P4502E1上调。在培养中用LPS刺激时，与对照大鼠相比，库普弗细胞释放出更多的TNF-α；DLPC可减少这种增加。它还降低了ERK1/2和p38的磷酸化以及核因子-κB（NF-κB）的激活，同时降低了核p65的表达并增加了胞质IκB-α的表达。ERK1/2抑制剂PD098059可消除ERK1/2和NF-κB的激活。p38抑制剂SB203580可消除p38的激活，而不影响NF-κB。两种抑制剂均减少了TNF-α的产生。因此，DLPC通过抑制p38和ERK1/2的激活来减少LPS依赖性TNF-α的产生；后者导致NF-κB激活减少。
