Quiroga Ariel D, de Lujan Alvarez Maria, Parody Juan P, Ronco Maria T, Carnovale Cristina E, Carrillo Maria Cristina
Facultad de Ciencias Bioquimicas y Farmaceuticas, Instituto de Fisiologia Experimental, Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Universidad Nacional de Rosario, Rosario, Argentina.
Growth Factors. 2009 Aug;27(4):214-27. doi: 10.1080/08977190902951558.
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.
目前尚不清楚α-干扰素（IFN-α）如何预防肝癌发生。我们已经证明，IFN-α2b通过激活NADPH氧化酶诱导活性氧（ROS）形成，从而诱导肝细胞转化生长因子-β1（TGF-β(1)）的产生和分泌。这种TGF-β(1)会改变抗氧化防御并诱导程序性细胞死亡。由于已证明IFN-α通过激活p38丝裂原活化蛋白激酶（p38 MAPK）诱导细胞凋亡，本研究旨在评估该激酶在IFN-α2b诱导的大鼠肝前病变细胞凋亡中的作用；并进一步评估NADPH氧化酶的参与情况。在IFN-α2b诱导的大鼠肝前病变细胞凋亡过程中，p38 MAPK通路被激活。这种激活伴随着不同转录因子的磷酸化，这取决于IFN-α2b刺激的时间。我们的数据表明，NADPH氧化酶被IFN-α2b通过p38 MAPK激活。p38 MAPK诱导的NADPH氧化酶激活通过两步途径完成：首先，不依赖ROS；其次，依赖ROS和TGF-β(1)。
