Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin

Hepatology. 2013 Nov;58(5):1814-23. doi: 10.1002/hep.26419. Epub 2013 Sep 30.


Chronic plus binge ethanol feeding acts synergistically to induce liver injury in mice, but the mechanisms underlying this phenomenon remain unclear. Here, we show that chronic plus binge ethanol feeding synergistically up-regulated the hepatic expression of interleukin-1β and tumor necrosis factor alpha and induced neutrophil accumulation in the liver, compared with chronic or binge feeding alone. In vivo depletion of neutrophils through administration of an anti-Ly6G antibody markedly reduced chronic-binge ethanol feeding-induced liver injury. Real-time polymerase chain reaction analyses revealed that hepatic E-selectin expression was up-regulated 10-fold, whereas expression of other neutrophil infiltration-related adhesion molecules (e.g., P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1) was slightly up- or down-regulated in this chronic-binge model. The genetic deletion of E-selectin prevented chronic-binge ethanol-induced hepatic neutrophil infiltration as well as elevation of serum transaminases without affecting ethanol-induced steatosis. In addition, E-selectin-deficient mice showed reduced hepatic expression of several proinflammatory cytokines, chemokines, and adhesion molecules, compared to wild-type mice, after chronic-binge ethanol feeding. Finally, the expression of E-selectin was highly up-regulated in human alcoholic fatty livers, but not in alcoholic cirrhosis.

Conclusions: Chronic-binge ethanol feeding up-regulates expression of proinflammatory cytokines, followed by the induction of E-selectin. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury induced by chronic-binge feeding in mice and may also contribute to the pathogenesis of early stages of human alcoholic liver disease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Cytochrome P-450 CYP2E1 / genetics
  • E-Selectin / genetics
  • E-Selectin / physiology*
  • Humans
  • Intercellular Adhesion Molecule-1 / analysis
  • Interleukin-1beta / physiology
  • Liver / pathology*
  • Liver Diseases, Alcoholic / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Infiltration*
  • Tumor Necrosis Factor-alpha / physiology
  • Vascular Cell Adhesion Molecule-1 / analysis


  • E-Selectin
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Cytochrome P-450 CYP2E1
  • Alanine Transaminase