Cardiotrofina 1 una defensa natural del higado frente a la apoptosis

Resumen

CARDIOTROFINA-1: UNA DEFENSA NATURAL DEL HÍGADO FRENTE A LA APOPTOSIS RESUMEN: Apoptotic Tiver cell death in response to activation of the Fas pathway has been implicated in human liver diseases of various etiologies. IL-6 and the gpl30 family of cytokines have been reported as potent antiapoptotic cytokines. Recently, we have shown that cardiotrophin-1 (ct-1), a member of the gpl30 family, also displays potent ant apoptotic activities in the liver. However, the comparative role of these cytokines in the natural defence of the liver against pro-apoptotic stimulus has not yet been defined. %&/%&/ To address this point we have treated wild type (WT), CT-1-/- and IL-6-/- mice with lethal or sublethal doses of Fas agonist Jo-2 monoclonal antibody (mAb) and animal survival and liver damage were analyzed. We found that CT-1-/- mice exhibited a mortal ity of 50% in response to a dose of Jo-2 mAb that did not cause death of animáis in the other two groups. in addition, the liver damage evaluated by the level of serum transaminases, histopathological changes and apoptosis studies at 6 and 10 hours after Jo-2 administration was significantly increased in CT-1-/- mice as compared to both IL-6-/- and WT animals. Because STAT-3 has been established to be an important hepatoprotective molecule in this kind of liver damage we evaluated the activation of STAT-3 in the two groups of animáis. CT-1-/- mice showed, as compared to WT, a decreased activation of STAT-3 at 6 hours after anti-Fas injection. Interestingly, IL-6 mRNA was markedly upregulated after anti-Fas challenge in CT-1-/- mice despite the occurrence of intense liver damage, suggesting that overexpression of endogenous IL-6 afforded little activation of STAT3 in these animals. Treatment with recombinant CT-1 1 hour before Jo-2 mAb administration significantly reduced liver injury in CT-1-/-, IL-6-/- and WT mice, indicating that CT-1 can protect the liver against proapototic stimuli in this experimental model. In addition, the livers from WT and CT-1-/- were analyzed by proteomic and genomic. The proteomic analysis did not reveal quantitative differences between the livers of CT-1-/- mice and wild type mice but show the appearance of isoforms with more basic a iso-electric point in 6 proteins in the case of CT-1-/- mice. The microarray expression analysis in the livers of mice CT-1-/- and WT mice show changes in the expression of 52 well-known genes. Of these, 8 have been related to the sensitivity against processes of cellular death. Among them the diminution of 9 times in the expression of Igfbpl in CT-1-/- livers respect to WT livers is one of the more remarkable difference. IGFBP1 has been described like a protein with anti-apoptotic effects in the liver damage mediate by Fas. In conclusion, we found that CT-1 plays a critical role in liver protection against propapoptotic challenge. Our data reveal an as yet unrecognized role of CT-1 in the natural defense of the liver against Fas-induced cell death