Apoptosis in B lymphocytes: The WEHI‐231 perspective

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Abstract
In this review we summarize recent work on the molecular basis of apoptosis in the murine B cell lymphoma WEHI-231. WEHI-231 cells undergo apoptosis in response to antigen receptor cross-linking with anti-Ig reagents. Death is specifically triggered via surface IgM (sIgM); cross-linking sIgD, Ia or FcR has no effect. Apoptosis is preceded by growth arrest in the Go/G1 phase of the cell cycle and may not occur in all currently available WEHI-231 sublines. The continuous passage of WEHI-231 cells in different laboratories has yielded variants that differ greatly in their response to anti-Ig treatment because apoptotic cells tend to be negatively selected in culture. Resistant and susceptible variants undergo growth arrest in response to anti-Ig but only susceptible cells go on to die by apoptosis. Cells resistant to anti-Ig have intact apoptotic machinery as indicated by their susceptibility to dexamethasone, irradiation and other treatments. However, anti-Ig-resistant cells are also resistant to apoptosis induced by the immunosuppressants cyclosporin A, FK-506 and rapamycin. We discuss the experimental evidence indicating that the apoptotic machinery in WEHI-231 cells is pre-activated but under constant negative regulation by short-lived protein inhibitors. Inhibition is removed by a mediator released in response to anti-Ig treatment in susceptible sublines. The mediator of death is the sphingosine derivative, ceramide, presumably produced by membrane sphingomyelinases activated by anti-Ig. A hypothetical model on how ceramide kills WEHI-231 is presented.