PREFERENTIAL INDUCTION OF APOPTOSIS IN MOUSE CD4(-BETA-TCR(LO)CD3-EPSILON(LO) THYMOCYTES BY ZINC()CD8(+)ALPHA)

High concentrations of zinc salts (500 mu M and greater) are known to inhibit apoptosis in a variety of systems. However, closer examination of dose effects revealed that lower concentrations of zinc (80-200 mu M) could induce apoptosis in approximately 30-40% of mouse thymocytes following 8 h incubation. The ability of zinc to cause thymocyte apop tosis was detected flow-cytometrically by reductions in propidium iodi de DNA fluorescence and forward scatter, both quantitative indicators of apoptotic death. Zinc induced both internucleosomal DNA fragmentati on and morphological changes characteristic of apoptosis as determined by gel electrophoresis and electron microscopy, respectively. In addi tion, transcriptional and translational inhibitors prevented zinc-indu ced apoptosis, indicating a requirement for de novo mRNA and protein s ynthesis, another characteristic of apoptotic death. Fluorescent immun ophenotype-specific apoptotic analysis indicated that zinc-induced apo ptosis occurred primarily in the less mature CD4(+)CD8(+)alpha beta TC R(lo)CD3 epsilon(lo) thymocyte subset, with lower amounts of death occ urring in the other subsets. This lineage specificity was shared with glucocorticoid-induced apoptosis. Taken together, these results indica te that zi nc induces true apopotitic death in mouse thymocytes and su ggests a role for zinc in the regulation of apoptosis. (C) 1995 Wiley- Liss, Inc.