Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes
- 1 June 2003
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 37 (6), 1425-1434
- https://doi.org/10.1053/jhep.2003.50230
Abstract
We previously reported that depletion of glutathione in murine hepatocytes by diethylmaleate (DEM) or acetaminophen (APAP) leads to oxidative stress-dependent necrosis and sensitizes to tumor necrosis factor (TNF)-induced apoptosis in an oxidative stress-independent fashion, which could not be explained by interference with nuclear factor kappaB (NF-kappaB) nuclear translocation. The present report explores the mechanisms of these effects. We observed that DEM led to necrosis when both mitochondrial and cytosol glutathione were depleted profoundly but sensitized to TNF-induced apoptosis when cytosol glutathione was depleted selectively. DEM and APAP lead to a significant decrease in reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Glutathione depletion by DEM or APAP was associated with inhibition of TNF-induced NF-kappaB transactivation of anti-apoptotic genes, including inducible nitric oxide synthase (i-NOS). Provision of exogenous NO partially abrogated the sensitization to TNF in response to glutathione depletion. Glutathione depletion alone led to sustained increase in phospho-jun levels and c-Jun-N-terminal kinase (JNK) activity. JNK inhibitor partially blocked the sensitization to TNF-induced apoptosis accompanying glutathione depletion. In conclusion, these findings suggest that extramitochondrial glutathione depletion alters the thiol-disulfide redox state, leading to inhibition of NF-kappaB transactivation of survival genes and to sustained activation of JNK, both of which contribute to the sensitization to TNF-induced apoptosis.Keywords
This publication has 34 references indexed in Scilit:
- Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytesHepatology, 2002
- Biochemical and Cellular Mechanisms of Toxic Liver InjurySeminars in Liver Disease, 2002
- Chronic Ethanol Exposure Potentiates Lipopolysaccharide Liver Injury Despite Inhibiting Jun N-terminal Kinase and Caspase 3 ActivationPublished by Elsevier BV ,2002
- NF-κB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-α– and Fas-mediated apoptosisGastroenterology, 2001
- Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factorGastroenterology, 1998
- NFkappaB prevents apoptosis and liver dysfunction during liver regeneration.JCI Insight, 1998
- Mitochondrial Glutathione: Importance and TransportSeminars in Liver Disease, 1998
- A High-Performance Liquid Chromatography Method for Measurement of Oxidized Glutathione in Biological SamplesAnalytical Biochemistry, 1994
- Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol.JCI Insight, 1987
- Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissuesAnalytical Biochemistry, 1969