Abstract
We previously reported that dilinoleoylphosphatidylcholine (DLPC) decreases lipopolysaccharide-induced TNF-alpha generation by Kupffer cells of ethanol-fed rats by blocking p38, ERK1/2, and NF-kappaB activation. Here we show that DLPC also decreases TNF-alpha induction by acetaldehyde, a toxic metabolite released by ethanol oxidation. Acetaldehyde induces TNF-alpha generation with a maximal effect at 200 microM and activates p38 and ERK1/2; the latter in turn activates NF-kappaB. This effect is augmented in Kupffer cells of ethanol-fed rats, with upregulation of cytochrome P4502E1 by ethanol. DLPC decreases TNF-alpha generation by blocking p38, ERK1/2, and NF-kappaB activation. Likewise, SB203580, which abolishes p38 activation, and PD098059, which abrogates ERK1/2 and NF-kappaB activation, diminish TNF-alpha generation. Since increased TNF-alpha generation plays a pathogenic role in alcoholic liver disease, the DLPC action on Kupffer cells may explain, in part, its beneficial effects on liver cell injury after ethanol consumption.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetaldehyde / metabolism*
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Animals
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Cells, Cultured
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Cytochrome P-450 CYP2E1 / metabolism
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Diet
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Enzyme Inhibitors / pharmacology
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Ethanol / administration & dosage*
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Ethanol / metabolism
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Flavonoids / pharmacology
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Imidazoles / pharmacology
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Kupffer Cells / cytology
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Kupffer Cells / drug effects*
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Kupffer Cells / metabolism
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Male
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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NF-kappa B / metabolism
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Phosphatidylcholines / metabolism
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Phosphatidylcholines / pharmacology*
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Tumor Necrosis Factor-alpha / metabolism*
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p38 Mitogen-Activated Protein Kinases
Substances
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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NF-kappa B
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Phosphatidylcholines
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Pyridines
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Tumor Necrosis Factor-alpha
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Ethanol
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1,2-linoleoylphosphatidylcholine
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Cytochrome P-450 CYP2E1
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Acetaldehyde
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one