Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin

Gastroenterology. 1998 Aug;115(2):443-51. doi: 10.1016/s0016-5085(98)70211-2.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute-Phase Proteins*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Calcium / metabolism
  • Carrier Proteins / metabolism
  • Cell Separation
  • Drug Tolerance / physiology
  • Endotoxins / blood
  • Endotoxins / pharmacology*
  • Ethanol / blood
  • Ethanol / pharmacology*
  • Female
  • Intracellular Membranes / metabolism
  • Kupffer Cells / drug effects*
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / pharmacology
  • Liver / drug effects
  • Liver / pathology
  • Membrane Glycoproteins*
  • Osmolar Concentration
  • Rats
  • Rats, Sprague-Dawley
  • Transaminases / blood
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Acute-Phase Proteins
  • Anti-Bacterial Agents
  • Carrier Proteins
  • Endotoxins
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Tumor Necrosis Factor-alpha
  • lipopolysaccharide-binding protein
  • Ethanol
  • Transaminases
  • Calcium