Interferon alfa-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic Transforming Growth Factor b1 (TGFb1)

ALVAREZ, MARIA DE LUJAN; RONCO, MARIA TERESA; OCHOA, JUSTINA OCHOA; MONTI, JUAN ALBERTO; CARNOVALE, CRISTINA ESTER; QUIROGA, ARIEL DARIO; PISANI, GERARDO BRUNO; LUGANO, MARÍA CRISTINA; CARRILLO, MARÍA CRISTINA

Nueva Delhi, India

Congreso; 14th Biennial Conference of the Asian Pacific Association for the study of the Liver (APASL); 2004

“Interferon alfa-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic Transforming Growth Factor b1 (TGFb1).” ML Alvarez, MT Ronco, JE Ochoa, JA Monti, CE Carnovale, AD Quiroga, GB Pisani; MC Lugano, MC Carrillo. Journal of Gastroenterology and Hepatology 19 (Suppl.), pag. 754; 2004. It has been reported that Interferon alfa-2b (IFN) reduces number and volume of rat hepatic preneoplastic foci, by increasing apoptosis on the foci. The aim of this work was to study if TGFâ1 mediates the apoptotic effect of IFN. Adult male Wistar rats were divided into 4 groups: subjected to a 2-phase model of preneoplasia development (G1), treated with IFN during: a) the 2 phases (G2), b) initiation (G3), and c) promotion (G4). Serum TGFâ1 levels were increased in IFN-treated rats. Immunohistochemical studies showed that IFN significantly increased the quantity of TGFâ1-positive hepatocytes per 1000 hepatocytes (G1= 13±2; G2= 26±3*; G3= 29±2*; G4= 32±6*). Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. In order to determine the source of TGFâ1, isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals of G1 were cultivated with or without IFN. IFN stimulus induced 13-fold increase of TGFâ1 secretion from hepatocytes. IFN- treated Kupffer cells and peritoneal macrophages did not secrete detectable TGFâ1 levels. IFN-stimulated cultured hepatocytes from preneoplastic livers showed elevated apoptosis, measured by fluorescence microscopy and caspase-3 activity (% apoptotic hepatocytes: without IFN= 8.5±0.6, with IFN= 16.2±0.4*, *p<0,05). They presented higher nuclear accumulation of p-Smads-2/3, indicating significant increase of TGFb1 signaling. When anti-TGFb1 was added to the culture media, TGFb1 activation and apoptosis induced by IFN were blocked. In conclusion, IFN-induced production of TGFâ1 by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci.