Interferon alpha-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor beta(1).

In previous work we showed that interferon alfa-2b (IFN-alpha2b) increases apoptosis on rat hepatic preneoplastic foci. The aim of this study was to determine if transforming growth factor beta1 (TGF-beta1) was involved in the programmed cell death on the foci. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine plus 2-acetylaminofluorene) of preneoplasia development (group 1); treated with IFN-alpha2b during the 2 phases (group 2); treated with IFN-alpha2b during initiation with diethylnitrosamine (group 3); treated with IFN-alpha2b during 2-acetylaminofluorene administration (group 4); subjected only to an initiation stage (group 5); and treated with IFN-alpha2b during the initiation period (group 6). Serum TGF-beta1 levels were increased in IFN-alpha2b-treated rats. Immunohistochemical studies showed that IFN-alpha2b significantly increased the quantity of TGF-beta1-positive hepatocytes in groups 2 to 4. Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. To determine the source of TGF-beta1, isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals in groups 1 and 5 were cultured with or without IFN-alpha2b. IFN-alpha2b stimulus induced several-fold increases of TGF-beta1 secretion from hepatocytes. Neither Kupffer cells nor peritoneal macrophages secreted detectable TGF-beta1 levels when they were treated with IFN-alpha2b. IFN-alpha2b-stimulated cultured hepatocytes from preneoplastic livers showed enhanced apoptosis, measured by fluorescence microscopy and caspase-3 activity. They presented higher nuclear accumulation of p-Smads-2/3, indicating increased TGF-beta1 signaling. When anti-TGF-beta1 was added to the culture media, TGF-beta1 activation and apoptosis induced by IFN-alpha2b were blocked. In conclusion, IFN-alpha2b-induced production of TGF-beta1 by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci.

de Luján Alvarez M ，Ronco MT ，Ochoa JE ，Monti JA ，Carnovale CE ，Pisani GB ，Lugano MC ，Carrillo MC ... -  《HEPATOLOGY》

Cross-talk between IFN-alpha and TGF-beta1 signaling pathways in preneoplastic rat liver.

Alvarez Mde L ，Quiroga AD ，Parody JP ，Ronco MT ，Francés DE ，Carnovale CE ，Carrillo MC ... -  《-》

Time-dependent onset of Interferon-alpha2b-induced apoptosis in isolated hepatocytes from preneoplastic rat livers.

Alvarez Mde L ，Quiroga AD ，Ronco MT ，Parody JP ，Ochoa JE ，Monti JA ，Carnovale CE ，Carrillo MC ... -  《CYTOKINE》

Involvement of reactive oxygen species on the apoptotic mechanism induced by IFN-alpha2b in rat preneoplastic liver.

Quiroga AD ，Alvarez Mde L ，Parody JP ，Ronco MT ，Francés DE ，Pisani GB ，Carnovale CE ，Carrillo MC ... -  《BIOCHEMICAL PHARMACOLOGY》

The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein.

de Luján Alvarez M ，Cerliani JP ，Monti J ，Carnovale C ，Ronco MT ，Pisani G ，Lugano MC ，Carrillo MC ... -  《HEPATOLOGY》