Time-dependent onset of Interferon-a2b-induced apoptosis in isolated hepatocytes from preneoplastic rat livers

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2006-12, Vol.36 (5-6), p.245-253
• Main Authors: Alvarez, Maria de Lujan, Quiroga, Ariel D, Ronco, Maria Teresa, Parody, Juan Pablo, Ochoa, J Elena, Monti, Juan A, Carnovale, Cristina E, Carrillo, Maria Cristina
• Format: Article
• Language: English
• ISSN: 1043-4666
• DOI: 10.1016/j.cyto.2007.01.002

We have already demonstrated that interferon alfa-2b (IFN-a2b) induces apoptosis in isolated hepatocytes from preneoplastic rat livers via the secretion of transforming growth factor b1 (TGF-b1), and this process is accompanied by caspase-3 activation. The aim of this study was to further investigate the mechanism of this activation. Isolated hepatocytes from preneoplastic livers induced DNA fragmentation in response to IFN-a2b, which was completely blocked when anti-TGF-b1 was added to the culture media. IFN-a2b mediated radical oxygen species (ROS) production that preceded the loss of mitochondrial transmembrane potential ( partial differential ), release of cytochrome c, and activation of caspase-3. Bax levels increased in a time-dependent fashion, and Bcl-xL was down-regulated in the early hours of IFN-a2b treatment. The delayed translocation of Bid into the mitochondria was in concordance with late caspase-8 activation. In conclusion, endogenous TGF-b1 secreted under IFN-a2b stimulus seems to induce cytochrome c release through a mechanism related to Bcl-2 family members and loss of mitochondrial partial differential . Bax protein could be responsible of the release of cytochrome c during the initial hours of IFN-a2b-induced apoptosis via TGF-b1. Activated Bid by caspases could amplificate the mitochondrial events, enhancing the release of cytochrome c.