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

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.