IDENTIFICATION OF IMMUNOSUPPRESSANT-INDUCED APOPTOSIS IN A MURINE B-CELL LINE AND ITS PREVENTION BY BCL-X BUT NOT BCL-2

Cyclosporin A, FK-506, and rapamycin are inmunosuppressants often used as pharmacological probes to study lymphocyte activation and physiological cell death (PCD). Because cyclosporin A and FK-506 are known to prevent PCD in T-cell hybridomas and thymocytes, we used these reagents, as well as rapamycin, to determine whether they alter the pathway leading to apoptosis in murine WEHI-231 cells following surface IgM cross-linking. We observed that the inmunosuppressants themselves induced PCD in WEHI-231 cells, but only in sublines susceptible to anti-IgM-mediated apoptosis. PCD was preceded by growth arrest and characterized by the DNA fragmentation pattern typical of apoptosis. In B-cell lines resistant to anti-immunoglobulin- and immunosuppressant-induced PCD, cyclosporin A, FK-506, and rapamycin caused growth arrest. PCD was also induced by inhibitors of protein synthesis in WEHI-231 cells but not in the mature B-cell line BAL-17. Immunosuppressant-induced and protein synthesis inhibitor-induced PCD, but not growth arrest, could be prevented by the overexpression of bcl-x(L), while transfection with bcl-2 did not affect PCD of cell cycle arrest. These results suggest that bcl-2 and bcl-x(L) may control partially independent systems to inhibit PCD in lymphoid cells and that PCD in B and T cells may be differentially regulated,