7,8-DIHYDRONEOPTERIN-INDUCED APOPTOSIS IN JURKAT T-LYMPHOCYTES - A COMPARISON WITH ANTI-FAS-MEDIATED AND HYDROGEN PEROXIDE-MEDIATED CELL-DEATH

Activated cell-mediated immunity, associated for example with HIV infe ction, is accompanied by elevated concentrations of neopterin and 7,8- dihydroneopterin. Recent data have indicated a role of neopterin deriv atives 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 kineti cs and sensitivity of apoptotic cell death of human leukemic Jurkat T cells to that of treatments with 7,8-dihydroneopterin, anti-Fas, and H 2O2. Upon incubation with 5 mM 7,8-dihydroneopterin and 50 mu M hydrog en peroxide over a period of 24 hr, bimodal kinetics were observed wit h 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 suppresse d 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 H 2O2 7,8-dihydroneopterin-mediated, and similarly anti-Fas- and H2O2-me diated, apoptosis was not inhibited by a broad range of pharmacologica l inhibitors, such as actinomycin D, cycloheximide, cyclosporin A, and various protein kinase inhibitors. On the contrary, inhibitors with a ntioxidant abilities, such as pyrrolidinedithiocarbamate, significantl y blocked 7,8-dihydroneopterin-, H2O2- as well as anti-Fas-mediated ap optosis. These results imply that 7,8-dihydroneopterin-, H2O2-, and an ti-Fas-mediated cell death might involve related redox sensitive signa l transduction pathways. (C) 1998 Elsevier Science Inc.