Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent.
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.
Camargo
C A
CA
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Madden
J F
JF
Gao
W
W
Selvan
R S
RS
Clavien
P A
PA
D000210:Acute-Phase Reaction / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D015152:Blotting, Northern; D002097:C-Reactive Protein / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase