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[Ethanol changes sensitivity of Kupffer cells to endotoxin]
Shunhei Yamashina1, Kenichi Ikejima, Nobuyuki Enomoto
1Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Nihon Arukoru Yakubutsu Igakkai Zasshi = Japanese Journal of Alcohol Studies & Drug Dependence
|December 3, 2003
Summary
Acute alcohol exposure causes temporary tolerance in Kupffer cells, impairing immune response. Later, it sensitizes these cells to endotoxin, worsening alcoholic liver injury. This explains the paradox in alcohol-induced liver damage.
Area of Science:
- Hepatology
- Immunology
- Toxicology
Background:
- Gut-derived endotoxin is a key factor in alcoholic liver injury (ALI).
- Antibiotics or Kupffer cell inactivation prevent early ALI, yet ethanol paradoxically inactivates isolated Kupffer cells.
- This review investigates the temporal effects of ethanol on Kupffer cell responses to endotoxin.
Purpose of the Study:
- To resolve the paradox of Kupffer cell involvement in ALI despite ethanol's inhibitory effect on isolated cells.
- To examine the time-dependent changes in Kupffer cell activation and signaling pathways following acute ethanol exposure.
Main Methods:
- Mice received intragastric ethanol, followed by lipopolysaccharide (LPS) injection at different time points.
- Kupffer cell responses (calcium concentration, TNF-alpha release, CD14 expression, IRAK/NF-kappa B activity) were assessed.
- Gut sterilization with antibiotics was used to confirm the role of endotoxin.
Main Results:
- Early ethanol exposure (1-2 hours) induced Kupffer cell tolerance to LPS, reducing inflammatory responses.
- Later ethanol exposure (21 hours) sensitized Kupffer cells to LPS, increasing inflammatory mediator production and signaling.
- Antibiotic pretreatment blocked these ethanol-induced changes, confirming the role of gut-derived endotoxin.
Conclusions:
- Acute ethanol exposure induces biphasic effects on Kupffer cells: early tolerance and later sensitization to endotoxin.
- Kupffer cell tolerance may impair innate immunity in alcoholism.
- Kupffer cell sensitization contributes to the progression of alcoholic liver injury.