Involvement of reactive oxygen species on the apoptotic mechanism induced by IFN-alpha2b in rat preneoplastic liver.
Interferon-alpha2b (IFN-alpha2b) is an important component in the preventive treatment of patients who have severe hepatic illness such as hepatitis B or C and hepatocarcinomas. In a previous work, using a rat liver preneoplastic model, we have demonstrated that IFN-alpha2b reduces the number and volume of altered hepatic foci (AHF) inducing apoptosis through a mechanism mediated by TGF-beta(1). In this study, the implication of hepatocytes redox status of IFN-alpha2b-treated preneoplastic liver in the TGF-beta(1)-induced apoptotic death was analyzed. Results indicate that IFN-alpha2b induces hepatocytic TGF-beta(1) production and secretion by induction of reactive oxygen species (ROS) formation through the activation of a membrane bound NADPH oxidase complex. TGF-beta(1), in turn, reduces hepatocytes antioxidant defenses and induces programmed cell death. On the other hand, it was also demonstrated that treatment of rats with IFN-alpha2b plus a ROS scavenger such as ascorbic acid, abolishes the apoptotic effect of IFN-alpha2b in rat preneoplastic livers, leading to an increase of the foci volume. In conclusion, these findings strongly suggest that ROS have a fundamental role as signaling and/or regulator molecules in the IFN-alpha2b-induced apoptosis in hepatic preneoplastic cells.
Quiroga
Ariel D
AD
Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Rosario, Rosario, Argentina.
Alvarez
María de Luján
Mde L
Parody
Juan P
JP
Ronco
María Teresa
MT
Francés
Daniel E
DE
Pisani
Gerardo B
GB
Carnovale
Cristina E
CE
Carrillo
María Cristina
MC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000166:cytology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D019255:NADPH Oxidases; D005982:Glutathione Transferase; D005978:Glutathione