Human T cell leukemia virus-I (HTLV-I) Tax-mediated apoptosis in activated T cells requires an enhanced intracellular prooxidant state.
We have shown that an estradiol-dependent activation of human T cell leukemia virus-I Tax leads to the inhibition of cell proliferation and to the induction of apoptosis. The present study demonstrates that a hormone-dependent activation of Tax promotes an enhanced prooxidant state in stably transfected Jurkat cells as measured by changes in the intracellular levels of glutathione and H2O2; these changes are followed by apoptotic cell death. Additional stimulation of the CD3/TCR pathway enhances the oxidative and apoptotic effects. Both Tax-mediated apoptosis and oxidative stress can be potently suppressed by antioxidants, as is seen with the administration of recombinant thioredoxin (adult T cell leukemia-derived factor) or pyrrolidine dithiocarbamate. Hormone-induced Tax activation induces a long-lasting activation of NF-kappaB, which is a major target of reactive oxygen intermediates. The long-term exposure of Jurkat cells to hormone eventually results in a selection of cell clones that have lost Tax activity. A subsequent transfection of these apparently "nonresponsive" clones allows the recovery of Tax responses in these cells. Our observations indicate that changes in the intracellular redox status may be a determining factor in Tax-mediated DNA damage, apoptosis, and selection against the long-term expression of Tax function.
Los
M
M
Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany.
Khazaie
K
K
Schulze-Osthoff
K
K
Baeuerle
P A
PA
Schirrmacher
V
V
Chlichlia
K
K
D000911:Antibodies, Monoclonal / Q000276:immunology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D016356:Gene Products, tax / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D019169:Jurkat Cells / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D000911:Antibodies, Monoclonal; D000975:Antioxidants; D017252:CD3 Complex; D016356:Gene Products, tax; D016877:Oxidants; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D004958:Estradiol