Glutathione depletion is involved in the inhibition of procollagen alpha1(I) mRNA levels caused by TNF-alpha on hepatic stellate cells.
TNF-alpha has been shown to inhibit procollagen alpha1(I) expression in hepatic stellate cells (HSC), although the molecular mechanisms involved have not been fully established. In the present work, we studied the possible role played by oxidative stress and NFkappaB on the antifibrogenic action of TNF-alpha on a cell line of rat HSC. Treatment of HSC with TNF-alpha did not affect either intracellular levels of reactive oxygen species or lipid peroxidation, but caused a decrease on reduced glutathione (GSH) levels. Restoration of intracellular GSH by incubation with exogenous GSH prevented the inhibition of procollagen alpha1(I) levels caused by TNF-alpha. The effect of GSH was not mimicked by antioxidants like deferoxamine, tempol or trolox. Activation of NFkappaB by TNF-alpha was also abolished by preincubation of HSC with GSH, but not by deferoxamine, tempol or trolox. These results point to GSH depletion as a mediator of TNF-alpha action in HSC.
Varela-Rey
Marta
M
Department of Biochemistry and Molecular Biology, University of Navarra, Pamplona, Spain.
Fontán-Gabás
Lorena
L
Blanco
Patricia
P
López-Zabalza
María J
MJ
Iraburu
María J
MJ
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione