Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent

Hepatology. 1997 Dec;26(6):1513-20. doi: 10.1002/hep.510260619.


Interleukin-6 (IL-6) is an acute reactant cytokine with anti-inflammatory properties, which has been found to prevent injury in a model of acute hepatitis in mice through downregulation of tumor necrosis factor alpha (TNF-alpha); to correlate inversely with markers of hepatocellular injury in patients with liver ischemia; and to initiate liver regeneration in mice. In this study, we investigated the role of IL-6 in rodent models of hepatic warm ischemia/reperfusion (WI/Rp) injury. IL-6-deficient mice (-/-) were subjected to hepatic WI and compared with C57BL/6 mice, as well as IL-6 -/- mice pretreated with recombinant IL-6 (rIL-6). The effects of rIL-6 following various periods of ischemia were further studied in models of hepatic ischemia in rats. IL-6 -/- mice had increased reperfusion injury as assessed by transaminase levels and a tissue necrosis scoring system when compared with controls, an effect prevented by pretreatment with rIL-6. Similarly, rats pretreated with rIL-6 had reduced reperfusion injury and better survival than controls in each respective WI group. Tissue TNF-alpha expression measured by Northern blot analysis and serum C-reactive protein (CRP) levels, a marker of inflammation, were significantly reduced in animals pretreated with rIL-6. Administration of antibodies to TNF-alpha reproduced the beneficial effect of rIL-6. Hepatocyte proliferation, as assessed by a scoring method for mitotic index and proliferating nuclear cell antigen staining, was markedly increased in rIL-6-treated rats when compared with controls. In conclusion, this study suggests that IL-6 could play an important role in limiting hepatic warm ischemia/reperfusion (WI/Rp) injury, probably through its anti-inflammatory properties, modulation of TNF-alpha, and/or promotion of liver regeneration. rIL-6 might become an important cytokine in clinical situations associated with WI/Rp injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Reaction / blood
  • Alanine Transaminase / blood
  • Animals
  • Antibodies / pharmacology
  • Aspartate Aminotransferases / blood
  • Blotting, Northern
  • C-Reactive Protein / metabolism
  • Cell Adhesion / drug effects
  • Cell Division / drug effects
  • Interleukin-6 / pharmacology
  • Interleukin-6 / physiology*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Circulation / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Proliferating Cell Nuclear Antigen / analysis
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Survival Rate
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies
  • Interleukin-6
  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • C-Reactive Protein
  • Aspartate Aminotransferases
  • Alanine Transaminase