Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice.
OBJECTIVE
The biological effects of ischaemic preconditioning include NF-kappaB 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-kappaB 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 microg/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.
Teoh
Narci
N
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
Field
Jacqueline
J
Farrell
Geoffrey
G
D000818:Animals; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D007511:Ischemia; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000473:pathology; D008102:Liver Circulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D015427:Reperfusion Injury / Q000517:prevention & control*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency
D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha