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 CCl(4)-treated rat livers. We observed an increase in the expression of catalase in activated SCs. Treatment with transforming growth factor-beta (TGF-beta) increased the production of H(2)O(2). Treatment with catalase decreased TGF-beta expression. Addition of H(2)O(2) resulted in increased TGF-beta production. 3-Amino-1,2,4-triazole abolished the capacity of SCs to remove H(2)O(2). 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-beta production. A paradoxical decrease of TGF-beta production was observed with diethyl maleate. Treatment of the cells with N-acetylcysteine resulted in increased TGF-beta production. TGF-beta decreased the capacity of the SCs to remove H(2)O(2.) An increase in the capacity to remove H(2)O(2) was observed when TGF-beta was removed by neutralizing antibodies. In conclusion, our results suggest: 1) a link between cellular GSH levels and TGF-beta production and 2) that cellular GSH levels discriminate whether H(2)O(2) is the result of oxidative stress or acts as second messenger in the TGF-beta signal transduction pathway.
Highlights
Increasing experimental evidence suggests that reactive oxygen species (ROS)1 such as H2O2, O2., and OH1⁄7, are implicated in the development and progress of several diseases, including Alzheimer’s disease [1], multiple sclerosis [2], human immunodeficiency virus [3], and liver fibrosis (4 – 6)
Our results suggest a model in which cellular GSH levels discriminate whether H2O2 is considered as oxidative stress or as second messenger in the TGF- signal transduction pathway
Northern Hybridization Analysis—First, we examined by Northern hybridization analysis the mRNA steady state levels of catalase, GSHPx, Cu/Zn-SOD, and Mn-SOD in freshly isolated stellate and parenchymal cells from both normal and CCl4-treated rat livers and in stellate cells kept in culture for 3, 6, and 12 days
Summary
Increasing experimental evidence suggests that reactive oxygen species (ROS) such as H2O2, O2., and OH1⁄7, are implicated in the development and progress of several diseases, including Alzheimer’s disease [1], multiple sclerosis [2], human immunodeficiency virus [3], and liver fibrosis (4 – 6). Stellate cells proliferate and undergo transition into myofibroblast-like cells, secreting large amounts of extracellular matrix components. This process is driven to a large extent by the autocrine and paracrine secretion of TGF- [9]. ROS and, in particular H2O2, have been proposed to act as signaling mediators for a variety of growth factors such as tumor necrosis factor, interleukin 1 [14], and TGF- [12] Both nuclear factor (NF)-B and activator protein-1 were shown to be regulated by the intracellular redox state [15, 16]. Our results suggest a model in which cellular GSH levels discriminate whether H2O2 is considered as oxidative stress or as second messenger in the TGF- signal transduction pathway
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