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

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Abstract
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 α (TNF‐α); 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‐α 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‐α 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‐α, and/or promotion of liver regeneration. rIL‐6 might become an important cytokine in clinical situations associated with WI/Rp injury.

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