title: Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning.
abstract: 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.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), Clinica Universitaria and Medical School, University of Navarra, Pamplona 31008, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Iñiguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Ansó
authors.forename: Matilde
authors.initials: M
authors.lastname: Bustos
authors.forename: Puri
authors.initials: P
authors.lastname: Fortes
authors.forename: Diane
authors.initials: D
authors.lastname: Pennica
authors.forename: Matias A
authors.initials: MA
authors.lastname: Avila
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019194:Ischemic Preconditioning; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D000906:Antibodies; D016207:Cytokines; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020122:tert-Butylhydroperoxide; C092073:cardiotrophin 1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3