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Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice

  • Narci Teoh
    Affiliations
    Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
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  • Jacqueline Field
    Affiliations
    Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
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  • Geoffrey Farrell
    Correspondence
    Corresponding author. Address: The Canberra Hospital, Australian National University, Yamba Drive, Garran, ACT 2605, Australia. Tel.: +61 2 6244 2195; fax: +61 2 6281 5179.
    Affiliations
    Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
    Search for articles by this author
Published:March 16, 2006DOI:https://doi.org/10.1016/j.jhep.2006.01.039

      Background/Aims

      The biological effects of ischaemic preconditioning include NF-κB activation, increased TNF synthesis, stimulation of cell cycle entry and hepatoprotection against ischaemia-reperfusion (IR) injury. Low dose TNF initiates the priming phase of liver regeneration via NF-κB and IL-6. To determine whether (1) IL-6 is released during preconditioning and confers protection against hepatic IR injury, and (2) IL-6 could mediate the biological effects of preconditioning.

      Methods

      Wildtype (wt) and TNF−/− C57BL6 mice were subjected to 90 min partial hepatic ischaemia and 2–44 h reperfusion with or without prior 10 min ischaemic preconditioning. To restitute liver injury, TNF−/− mice were administered murine TNF 5 μg/kg iv 1 min prior to IR. Murine recombinant IL-6 (500 ng/kg iv) was administered 30 min prior to IR, either to wt mice or to TNF−/−-repleted mice; in the latter case, 1 min before preconditioning.

      Results

      In wt mice, IL-6 attenuated hepatic IR injury and stimulated cell cycle entry. IR injury in TNF-repleted TNF−/− mice was not ameliorated by preconditioning. However, prior IL-6 administration conferred hepatoprotection (IL-6/preconditioned: 349 ± 169 U/L vs vehicle/preconditioned: 1250 ± 608 U/L, P < 0.01).

      Conclusions

      IL-6 is one likely mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning.

      Keywords

      Abbreviations::

      ALT (alanine aminotransferase), EMSA (electromobility (gel) shift assay), IL-6 (interleukin-6), IR (ischaemia-reperfusion), NF-κB (nuclear factor-kappa B), PCNA (proliferating cell nuclear antigen), STAT3 (signal transducer and activator of transcription 3), TNF (tumour necrosis factor), TNF−/− (tumour necrosis factor-α knockout mice)
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