title: A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide.
abstract: BACKGROUND
  Proinflammatory cytokines play an important role in alcohol-induced liver injury. The role of anti-inflammatory cytokines in the initiation and progression of alcoholic liver disease has received little attention. This study tested the hypothesis that an imbalance exists between pro- and anti-inflammatory cytokines in the liver during chronic exposure to alcohol. Alcohol exposure results in predominantly proinflammatory cytokine secretion and liver injury.
  
  
  METHODS
  IL-10 knock-out and their C57BL/6J counterpart wild-type mice were fed alcohol in drinking water for 7 weeks. At the end of alcohol feeding, Gram-negative bacterial lipopolysaccharide (LPS) was administered, and the animals were killed after 3 and 8 hr. Liver histology, plasma alanine aminotransferase and aspartate aminotransferase activity, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-10 levels, and liver cytokine messenger RNA levels were measured.
  
  
  RESULTS
  Alcohol feeding and LPS treatment did not change plasma enzyme activity levels in wild-type mice. In the IL-10 knock-out mice, LPS alone increased aspartate aminotransferase and alanine aminotransferase enzyme activity, and this was potentiated by alcohol. Alcohol induced liver steatosis in both wild-type and knock-out mice. LPS markedly enhanced the histological effects further, especially in the knock-out mice, with the emergence of focal necrosis, polymorphonuclear infiltration, and microabscesses in the liver. Plasma tumor necrosis factor-alpha and IL-1beta levels were not affected by alcohol alone. Proinflammatory cytokine levels were increased by LPS and further enhanced by alcohol treatment, particularly in the IL-10 knock-out mice. IL-10 plasma levels in the wild-type animals were down-regulated by alcohol. Changes in liver cytokine messenger RNA paralleled those seen in plasma cytokine levels.
  
  
  CONCLUSIONS
  Alcohol-induced liver sensitization to LPS in wild-type mice may involve down-regulation of IL-10. This anti-inflammatory cytokine, known for its hepatoprotective effects, is secreted simultaneously with proinflammatory cytokines. IL-10 may also limit alcohol-induced liver damage by counteracting the effects of proinflammatory cytokines.
authors.affiliation: Department of Internal Medicine, Division of Digestive Diseases, A. B. Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Daniell B
authors.initials: DB
authors.lastname: Hill
authors.forename: Nympha B
authors.initials: NB
authors.lastname: D'Souza
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.forename: Ion V
authors.initials: IV
authors.lastname: Deaciuc
authors.forename: Willem J S
authors.initials: WJ
authors.lastname: de Villiers
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D020751:Alcohol-Induced Disorders / Q000201:enzymology / Q000276:immunology*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002492:Central Nervous System Depressants / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D000431:Ethanol / Q000494:pharmacology; D007114:Immunization; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002492:Central Nervous System Depressants; D016207:Cytokines; D008070:Lipopolysaccharides; D016753:Interleukin-10; D000431:Ethanol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase