7,8-Dihydroneopterin-induced apoptosis in Jurkat T lymphocytes: a comparison with anti-Fas- and hydrogen peroxide-mediated cell death.
Activated cell-mediated immunity, associated for example with HIV infection, is accompanied by elevated concentrations of neopterin and 7,8-dihydroneopterin. Recent data have indicated a role of neopterin derivatives in virus activation and apoptotic cell death, processes likely to involve the action of oxygen free radicals. Because T cell death in AIDS is likely to involve the Fas/Fas ligand system and the action of oxygen free radicals and 7,8-dihydroneopterin, we compared the kinetics and sensitivity of apoptotic cell death of human leukemic Jurkat T cells to that of treatments with 7,8-dihydroneopterin, anti-Fas, and H2O2. Upon incubation with 5 mM 7,8-dihydroneopterin and 50 microM hydrogen peroxide over a period of 24 hr, bimodal kinetics were observed with peaks at 5.5 hr (7,8-dihydroneopterin, 13.1%; H2O2, 11.4%) and at 24 hr (7,8-dihydroneopterin, 11.2%; H2O2, 13.2%). In contrast, anti-Fas (20 ng/mL)-induced apoptosis increased steadily over time, peaking at 11 hr (43.2%). Interestingly, anti-Fas-induced apoptosis was suppressed upon co-incubation with 7,8-dihydroneopterin and H2O2 by 62% and 68%, respectively. We also compared the sensitivity to drug treatments of apoptosis induced by 7,8-dihydroneopterin, anti-Fas antibodies, and H2O2. 7,8-Dihydroneopterin-mediated, and similarly anti-Fas- and H2O2-mediated, apoptosis was not inhibited by a broad range of pharmacological inhibitors, such as actinomycin D, cycloheximide, cyclosporin A, and various protein kinase inhibitors. On the contrary, inhibitors with antioxidant abilities, such as pyrrolidinedithiocarbamate, significantly blocked 7,8-dihydroneopterin-, H2O2- as well as anti-Fas-mediated apoptosis. These results imply that 7,8-dihydroneopterin-, H2O2-, and anti-Fas-mediated cell death might involve related redox sensitive signal transduction pathways.
Wirleitner
B
B
Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Australia.
Baier-Bitterlich
G
G
Böck
G
G
Widner
B
B
Fuchs
D
D
D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D019169:Jurkat Cells; D019798:Neopterin / Q000031:analogs & derivatives; D010766:Phosphorylation; D011621:Pteridines / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D011621:Pteridines; D019014:fas Receptor; C000976:7,8-dihydroneopterin; D014443:Tyrosine; D019798:Neopterin; D006861:Hydrogen Peroxide