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  • Title: Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin.
    Author: Enomoto N, Ikejima K, Bradford B, Rivera C, Kono H, Brenner DA, Thurman RG.
    Journal: Gastroenterology; 1998 Aug; 115(2):443-51. PubMed ID: 9679050.
    Abstract:
    BACKGROUND & AIMS: Ethanol causes both tolerance and sensitization of Kupffer cells. This study was designed to evaluate temporal effects of ethanol in an attempt to understand this paradox. METHODS: Rats were given ethanol (4 g/kg body wt) intragastrically, and Kupffer cells were isolated 0-48 hours later. After addition of lipopolysaccharide (LPS), intracellular calcium concentration ([Ca2+]i) was measured using a microspectrofluorometer with the fluorescent indicator fura-2, and tumor necrosis factor alpha (TNF-alpha) was measured by enzyme-linked immunosorbent assay. CD14 was evaluated by Western and Northern analysis. RESULTS: Two hours after ethanol administration, the LPS-induced increase in [Ca2+]i and TNF-alpha release by Kupffer cells was diminished by 50%, and these parameters were reciprocally enhanced twofold at 24 hours. Sterilization of the gut with antibiotics blocked all effects of ethanol on [Ca2+]i and TNF-alpha release completely. Twenty-four hours after ethanol, CD14 in Kupffer cells was elevated about fivefold. CONCLUSIONS: Kupffer cells isolated from rats early after ethanol exhibited tolerance to LPS, whereas sensitization was observed later. It is likely that both of these phenomena are caused by gut-derived endotoxin and that sensitization in Kupffer cells is caused by increases in CD14.
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