EGF blocks NADPH oxidase activation by TGF‐β in fetal rat hepatocytes, impairing oxidative stress, and cell death
- 5 December 2005
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 207 (2), 322-330
- https://doi.org/10.1002/jcp.20568
Abstract
Epidermal growth factor (EGF) is a survival signal for transforming growth factor‐beta (TGF‐β)‐induced apoptosis in hepatocytes, phosphatidylinositol 3‐kinase (PI 3‐K) being involved in this effect. Here, we analyze the possible cross talks between EGF and TGF‐β signals to understand how EGF impairs the early pro‐apoptotic events induced by TGF‐β. Data have indicated that neither SMAD nor c‐Jun NH2 Terminal Kinase (JNK) activations are altered by EGF, which clearly interferes with events directly related to the radical oxygen species (ROS) production, impairing oxidative stress, p38 MAP kinase activation, and cell death. Activation of a NADPH‐oxidase‐like system, which is responsible for the early ROS production by TGF‐β, is completely inhibited by EGF, through a PI 3‐K‐dependent mechanism. Activity of RAC1 increases by TGF‐β, but also by EGF, and both act synergistically to get maximum effects. Fetal rat hepatocytes express nox4, in addition to nox1 and nox2, and TGF‐β clearly upregulates nox4. EGF blocks up‐regulation of nox4 by TGF‐β. Interestingly, in the presence of PI 3‐K inhibitors, EGF is not able to counteract the nox4 upregulation by TGF‐β. Taking together these results indicate that impairment of TGF‐β‐induced NADPH oxidase activation by EGF is a RAC1‐independent process and correlates with an inhibition of the mechanisms that address the increase of nox4 mRNA levels by TGF‐β. J. Cell. Physiol. 207: 322–330, 2006.Keywords
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