Glutathione levels discriminate between oxidative stress and transforming growth factor-β signaling in activated rat hepatic stellate cells

Abstract

Reactive oxygen species are implicated in the pathogenesis of several diseases, including Alzheimer's disease, multiple sclerosis, human immunodeficiency virus, and liver fibrosis. With respect to liver fibrosis, we have investigated differences in antioxidant enzymes expression in stellate cells (SCs) and parenchymal cells from normal and CCl4-treated rat livers. We observed an increase in the expression of catalase in activated SCs. Treatment with transforming growth factor-β (TGF-β) increased the production of H2O2. Treatment with catalase decreased TGF-β expression. Addition of H2O2 resulted in increased TGF-β production. 3-Amino-1,2,4,- triazole abolished the capacity of SCs to remove H2O2. A paradoxical increase in capacity was observed when the cells were pretreated with diethyl maleate. Treatment with 3-amino-1,2,4-triazole increased TGF-β production. A paradoxical decrease of TGF-β production was observed with diethyl maleate. Treatment of the cells with N-acetylcysteine resulted in increased TGF-β production. TGF-β decreased the capacity of the SCs to remove H2O2. An increase in the capacity to remove H2O2 was observed when TGF-β was removed by neutralizing antibodies. In conclusion, our results suggest: 1) a link between cellular GSH levels and TGF-β production and 2) that cellular GSH levels discriminate whether H2O2 is the result of oxidative stress or acts as second messenger in the TGF-β signal transduction pathway.