Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats.
OBJECTIVE
Cardiotrophin-1 (CT-1) is a member of the interleukin 6 (IL-6) family of cytokines, which protect cardiac myocytes against thermal and ischemic insults. In this study, we investigated the expression of CT-1 by liver cells and its possible hepatoprotective properties.


METHODS
We analyzed the production, signaling, and antiapoptotic properties of CT-1 in hepatocytes and the expression of this cytokine during liver regeneration. We also investigated whether CT-1 might exert protective effects in animal models of liver damage.


RESULTS
We found that CT-1 is up-regulated during liver regeneration and exerts potent antiapoptotic effects on hepatocytic cells. Hepatocytes cultured under serum starvation or stimulated with the pro-apoptotic cytokine transforming growth factor beta (TGF-beta) produce CT-1, which behaves as an autocrine/paracrine survival factor. Treatment with an adenovirus encoding CT-1 efficiently protects rats against fulminant liver failure after subtotal hepatectomy, an intervention that causes 91% mortality in control animals whereas 54% of those receiving CT-1 gene therapy were long-term survivors. This protective effect was associated with reduced caspase-3 activity and activation of the antiapoptotic signaling cascades signal transducer and activator of transcription (Stat-3), extracellular regulated kinases (Erk) 1/2, and Akt in the remnant liver. Gene transfer of CT-1 to the liver also abrogated Concanavalin A (Con-A) liver injury and activated antiapoptotic pathways in the hepatic tissue. Similar protection was obtained by treating the animals with 5 microg of recombinant CT-1 given intravenously before Con-A administration.


CONCLUSIONS
We show that CT-1 is a hepatocyte survival factor that efficiently reduces hepatocellular damage in animal models of acute liver injury. Our data point to CT-1 as a new promising hepatoprotective therapy.
Bustos
Matilde
M
Department of Medicine, Division of Hepatology and Gene Therapy, Clinica Universitaria and Medical School, University of Navarra.
Beraza
Naiara
N
Lasarte
Juan-Jose
JJ
Baixeras
Elena
E
Alzuguren
Pilar
P
Bordet
Thierry
T
Prieto
Jesus
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular; D002470:Cell Survival / Q000502:physiology; D003208:Concanavalin A; D016207:Cytokines / Q000235:genetics* / Q000494:pharmacology*; D015316:Genetic Therapy; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D007275:Injections, Intravenous; D017093:Liver Failure / Q000139:chemically induced / Q000188:drug therapy*; D008113:Liver Neoplasms; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016207:Cytokines; D003208:Concanavalin A; C092073:cardiotrophin 1