Cloning and characterization of two novel zebrafish P2X receptor subunits |
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Authors: | Diaz-Hernandez Miguel Cox Jane A Migita Keisuke Haines William Egan Terrance M Voigt Mark M |
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Affiliation: | Alcohol Research and Treatment Center, Veterans Affairs Medical Center and Mount Sinai School of Medicine, Bronx, NY 10468, USA. |
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Abstract: | 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. |
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Keywords: | Dilinoleoylphosphatidylcholine TNF-α Lipopolysaccharide Kupffer cells Cytochrome P4502E1 NF-κB ERK1/2 p38 |
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