Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nucler factor-kappa B-dependent mechanism
Résumé
The transforming growth factor-beta (TGF-β) induces survival signals in foetal rat hepatocytes through transactivation of the epidermal growth factor receptor (EGFR). The molecular mechanism is not completely understood, but early activation of the TACE/ADAM17 (one of the metalloproteases involved in shedding of the EGFR ligands) and up-regulation of transforming growth factor alpha (TGF-α) and heparin binding epidermal growth factor-like growth factor (HB-EGF) appear to be involved. Here we have analyzed the molecular mechanisms that mediate up-regulation of the EGFR ligands by TGF-β in foetal rat hepatocytes. The potential involvement of reactive oxygen species (ROS), an early signal induced by TGF-β, and the existence of an amplification loop triggered by initial activation of the EGFR, have been studied. Results indicate that diphenyleneiodonium (DPI) and apocynin, two NADPH oxidase inhibitors, and SB431542, inhibitor of the TGF-β receptor I (TβR-I), block up-regulation of EGFR ligands and Akt activation. Different members of the NADPH oxidase family of genes are expressed in hepatocytes, included nox1, nox2 and nox4. TGF-β up-regulates nox4 and increases the levels of Rac1 protein, a known regulator of both Nox1 and Nox2, in a TβR-I-dependent manner. TGF-β mediates activation of the NF-κB pathway, which is inhibited by DPI and is required for up-regulation of TGF-α and HB-EGF. In contrast, EGFR activation is not required for TGF-β-induced up-regulation of those ligands. Considering previous works that established the role of ROS in the apoptosis induced by TGF-β in hepatocytes, results presented here indicate that ROS might mediate both pro- and anti-apoptotic signals in TGF-β-treated cells.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...