Pertussis toxin inhibits activation-induced cell death of human thymocytes, pre-B leukemia cells and monocytes.
Activation of human thymocytes and pre-B cells via the CD3/T cell receptor (TCR) complex or the IgM/B cell receptor complex, respectively, results in apoptotic cell death. Similarly, cross-linking of the activation marker CD69, which belongs to the natural killer complex, causes apoptosis of lipopolysaccharide-preactivated monocytes. Here we show that pertussis toxin (PTX) inhibits the activation-induced apoptosis of these three cell types, though it fails to prevent the programmed cell death that follows exposure of cells to the synthetic glucocorticoid dexamethasone (thymocytes, pre-B cells) or to interleukin 4 (monocytes). The capacity of pertussis toxin to suppress activation-induced death is not due to quenching of the activation signal, because thymocytes exposed to PTX are still capable of mobilizing Ca2+ after TCR-alpha/beta cross-linking and proliferate in response to costimulation with PTX and CD3/TCR ligation. The apoptosis-inhibitory effect of PTX depends on the presence of an intact adenosine diphosphate (ADP)-ribosylating moiety, since a mutant pertussis toxin molecule that lacks enzymatic activity, but still possesses the membrane translocating activity, fails to interfere with activation-induced cell death. A toxin that induces a different spectrum of ADP ribosylation than PTX, cholera toxin, fails to inhibit apoptosis. To suppress apoptosis, the intact PTX holotoxin must be added to cells before the lethal activation step; its addition 30 min after initial activation remains without effect on apoptosis. These data unravel a PTX sensitive signal transduction event that intervenes during an early step of activation-induced cell death of immune cells.
Ramírez
R
R
Unidad de Investigación, Hospital Reina Sofía, Córdoba, Spain.
Carracedo
J
J
Zamzami
N
N
Castedo
M
M
Kroemer
G
G
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D006801:Humans; D008213:Lymphocyte Activation; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D037342:Pertussis Toxin; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D017260:Receptor-CD3 Complex, Antigen, T-Cell; D010566:Virulence Factors, Bordetella; D011065:Poly(ADP-ribose) Polymerases; D037342:Pertussis Toxin