Interferon-alpha2b (IFN-alpha2b)-induced apoptosis is mediated by p38 MAPK in hepatocytes from rat preneoplastic liver via activation of NADPH oxidase.
It is still unclear how Interferon-alfa (IFN-alpha) acts on preventing the appearance of hepatocarcinogenesis. We have demonstrated that IFN-alpha2b induces hepatocytic transforming growth factor-beta1 (TGF-beta(1)) production and secretion by inducing reactive oxygen species (ROS) formation through the activation of NADPH oxidase. This TGF-beta(1), alters antioxidant defences and induces programmed cell death. Since it was demonstrated that IFN-alpha induces apoptosis through the activation of p38 mitogen-activated protein kinase (p38 MAPK), this study was aimed to assess the role of this kinase in the IFN-alpha2b-induced apoptosis in rat liver preneoplasia; and to further evaluate the participation of NADPH oxidase. p38 MAPK pathway was activated during the IFN-alpha2b-induced apoptosis in rat liver preneoplasia. This activation was accompanied with phosphorylation of different transcription factors, depending on the time of IFN-alpha2b stimulus. Our data suggest that NADPH oxidase is activated by IFN-alpha2b through p38 MAPK. p38 MAPK-induced activation of NADPH oxidase is accomplished by a two-step pathway: first, ROS-independent and second ROS- and TGF-beta(1)-dependent.
Quiroga
Ariel D
AD
Facultad de Ciencias Bioquimicas y Farmaceuticas, Instituto de Fisiologia Experimental, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Universidad Nacional de Rosario, Rosario, Argentina.
de Lujan Alvarez
Maria
M
Parody
Juan P
JP
Ronco
Maria T
MT
Carnovale
Cristina E
CE
Carrillo
Maria Cristina
MC
D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D011230:Precancerous Conditions; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016898:Interferon-alpha; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases