Bcl-xL rescues WEHI 231 B lymphocytes from oxidant-mediated death following diverse apoptotic stimuli.
Developing lymphocytes undergo extensive cell death during selection of the immune repertoire. We investigated the influence of bcl-xL, a member of the bcl-2 family of apoptosis regulatory genes, on apoptosis in a model system for negative selection in the B lymphoid lineage. Overexpression of bcl-xL in WEHI 231 immature mouse B cells blocked apoptosis triggered by cross-linking of surface IgM. bcl-xL-transfected cells were also resistant to apoptosis following incubation in low serum medium or exposure to gamma-irradiation, the sphingomyelin ceramide, or compounds that increase intracellular levels of oxidants. Remarkably, the addition of antioxidants (catalase, N-acetylcysteine, or pyruvate) alone rescued the native WEHI 231 cells from apoptosis while having only minor effects on the viability of cells overexpressing bcl-xL. Anti-IgM cross-linking, ceramide, and gamma-irradiation treatments elevated intracellular peroxide production, which was prevented by treatment with antioxidants. Cells overexpressing bcl-xL had a similar rise in intracellular oxidants as control cells, indicating that bcl-xL modifies the cell's response to oxidants while having no detectable influence on the endogenous production of oxidants following apoptotic stimuli. These data implicate bcl-xL as a potent death repressor in B lymphocytes and support the hypothesis that bcl-xL regulates survival decisions within susceptible cells by functioning downstream of oxidant production.
Fang
W
W
Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
Rivard
J J
JJ
Ganser
J A
JA
LeBien
T W
TW
Nath
K A
KA
Mueller
D L
DL
Behrens
T W
TW
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects*; D002460:Cell Line; D002518:Ceramides / Q000633:toxicity; D005720:Gamma Rays / Q000009:adverse effects; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species / Q000633:toxicity*; D014162:Transfection; D051020:bcl-X Protein
D000975:Antioxidants; C494812:Bcl2l1 protein, mouse; D002518:Ceramides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051020:bcl-X Protein