Time-dependent onset of Interferon alfa-2b-induced apoptosis on rat preneoplastic hepatocytes

ALVAREZ, MARIA DE LUJAN; QUIROGA, ARIEL DARIO; RONCO, MARIA TERESA; PARODY, JUAN PABLO; OCHOA, JUSTINA OCHOA; MONTI, JUAN ALBERTO; CARNOVALE, CRISTINA ESTER; CARRILLO, MARÍA CRISTINA

CYTOKINE.

Año: 2006 vol. 36 p. 245 - 253

1043-4666

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 (DW), release of cytochromea2b) 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 (DW), release of cytochromeb1 (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 (DW), release of cytochromea2b, 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 (DW), release of cytochromeDW), 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 DW. 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., 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 DW. 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.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 DW. 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.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 DW. 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.DW. 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.a2b-induced apoptosis via TGF-b1. Activated Bid by caspases could amplificate the mitochondrial events, enhancing the release of cytochrome c.c. 2007 Elsevier Ltd. All rights reserved.2007 Elsevier Ltd. All rights reserved.