APOPTOSIS IN B-LYMPHOCYTES - THE WEHI-231 PERSPECTIVE

In this review we summarize recent work on the molecular basis of apop tosis in the murine B cell lymphoma WEHI-231. WEHI-231 cells undergo a poptosis in response to antigen receptor cross-linking with anti-Ig re agents. 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 G(0)/G(1) phase of the cell cycle and may not occur in all currently available WEHI-231 sublines. The continuous passage of W EHI-231 cells in different laboratories has yielded variants that diff er greatly in their response to anti-Ig treatment because apoptotic ce lls tend to be negatively selected in culture. Resistant and susceptib le variants undergo growth arrest in response to anti-Ig but only susc eptible cells go on to die by apoptosis. Cells resistant to anti-Ig ha ve intact apoptotic machinery as indicated by their susceptibility to dexamethasone, irradiation and other treatments. However, anti-Ig-resi stant cells are also resistant to apoptosis induced by the immunosuppr essants cyclosporin A, FK-506 and rapamycin. We discuss the experiment al 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 r esponse 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.