Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production.
BACKGROUND & AIMS: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) alpha are critical for progression of alcoholic liver injury. Thalidomide has been shown to suppress TNF-alpha production from macrophages. Accordingly, the purpose of this study was to determine whether thalidomide could prevent alcohol-induced liver injury. METHODS: Rats were given ethanol (5 g/kg body wt) and thalidomide (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-alpha was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. CD14 was determined by Western and fluorescence staining. RESULTS: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with thalidomide. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of thalidomide with ethanol prevented the KC sensitization completely. Furthermore, thalidomide abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by thalidomide. Moreover, thalidomide reduced the LPS-induced TNF-alpha production by KCs by decreasing TNF-alpha messenger RNA. CONCLUSIONS: These results collectively indicate that thalidomide prevents alcoholic liver injury through suppression of TNF-alpha production and abolishment of KC sensitization.
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alcoholic thalidomide Thalidomide thalidomide alcohol ethanol thalidomide ethanol Ca2+ Ca2+ thalidomide ethanol Thalidomide alcoholic tumor necrosis factor (TNF) alpha CD14 TNF-alpha TNF-alpha TNF-alpha TNF-alpha TNF-alpha ethanol CD14 TNF-alpha thalidomide ethanol thalidomide Ca2+ ethanol thalidomide thalidomide