Cardiotrophin-1 is an essential factor in the natural defense of the liver against apoptosis.
We previously reported that exogenous cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, exerts hepatoprotective effects. Because CT-1 is expressed in the normal liver, we hypothesized that this cytokine may constitute an endogenous defense of the liver against proapoptotic stimuli. Here, we found that CT-1-/- mice died faster than wild-type animals after challenge with a lethal dose of the Fas agonist Jo-2. At sublethal doses of Jo-2, all wild-type mice survived whereas CT-1-/- animals developed extensive hepatocyte apoptosis with 50% mortality at 24 hours. Pretreatment with CT-1 improved survival and reduced injury in both CT-1-/- and wild-type animals. Upon Fas ligation the activation of STAT-3, a molecule that defends the liver against apoptosis, was lower in CT-1-/- mice than in wild-type animals despite similar IL-6 up-regulation in the 2 groups. Analysis of liver transcriptome in CT-1-/- and wild-type mice showed that 9 genes reported to be associated with cell survival/death functions were differentially expressed in the 2 groups. Four of these genes [IGFBP1, peroxiredoxin3, TNFR1, and calpastatin (endogenous inhibitor of calpain)] could be validated by real-time PCR. All of them were down-regulated in CT-1-/- mice and were modulated by CT-1 administration. Treatment of CT-1-/- animals with the calpain inhibitor MDL28170 afforded significant protection against Fas-induced liver injury.


CONCLUSIONS
CT-1-/- mice are highly sensitive to Fas-mediated apoptosis due in part to deficient STAT-3 activation and inadequate control of calpain activity during the apoptotic process. Our data show that CT-1 is a natural defense of the liver against apoptosis. This cytokine may have therapeutic potential.
Marquès
Juan M
JM
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
Belza
Idoia
I
Holtmann
Bettina
B
Pennica
Diane
D
Prieto
Jesus
J
Bustos
Matilde
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology*; D008099:Liver / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010544:Peroxidases / Q000235:genetics / Q000502:physiology; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D019014:fas Receptor / Q000276:immunology
D000906:Antibodies; D002135:Calcium-Binding Proteins; D016207:Cytokines; C491899:Fas protein, mouse; C516116:Prdx3 protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C506236:Tnfrsf1a protein, mouse; D019014:fas Receptor; C033668:calpastatin; C092073:cardiotrophin 1; D010544:Peroxidases; D061105:Peroxiredoxin III; D054464:Peroxiredoxins