The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20061421
The Journal of Experimental Medicine, Vol. 203, No. 13, 2809-2815
The Rockefeller University Press, 0022-1007 $30.00
© Iñiguez et al.
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BRIEF DEFINITIVE REPORT

 Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning

Maria Iñiguez1, Carmen Berasain1, Eduardo Martinez-Ansó1, Matilde Bustos1, Puri Fortes1, Diane Pennica2, Matias A. Avila1, and Jesús Prieto1

1 Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), Clinica Universitaria and Medical School, University of Navarra, Pamplona 31008, Spain
2 Molecular Oncology Department, Genentech Inc., South San Francisco, CA 94080

CORRESPONDENCE Jesus Prieto: jprieto{at}unav.es OR Matias A Avila: maavila{at}unav.es

Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1–deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun–NH2-terminal kinase activation after I/R in normal mice but not in CT-1–null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti–CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1–null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6–deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1–null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP.

M.A. Avila and J. Prieto are senior authors on this paper.


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