Gottschalk A R, Boise L H, Thompson C B, Quintáns J
Department of Pathology, University of Chicago, IL 60637.
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7350-4. doi: 10.1073/pnas.91.15.7350.
Cyclosporin A, FK-506, and rapamycin are immunosuppressants 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 immunosuppressants 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-xL, while transfection with bcl-2 did not affect PCD or cell cycle arrest. These results suggest that bcl-2 and bcl-xL may control partially independent systems to inhibit PCD in lymphoid cells and that PCD in B and T cells may be differentially regulated.
环孢素A、FK-506和雷帕霉素是免疫抑制剂，常被用作药理学探针来研究淋巴细胞活化和生理性细胞死亡（PCD）。由于已知环孢素A和FK-506可防止T细胞杂交瘤和胸腺细胞发生PCD，我们使用这些试剂以及雷帕霉素来确定它们是否会改变小鼠WEHI-231细胞表面IgM交联后导致凋亡的途径。我们观察到免疫抑制剂本身可诱导WEHI-231细胞发生PCD，但仅在易受抗IgM介导凋亡的亚系中如此。PCD之前有生长停滞，其特征为典型的凋亡DNA片段化模式。在对抗免疫球蛋白和免疫抑制剂诱导的PCD有抗性的B细胞系中，环孢素A、FK-506和雷帕霉素会导致生长停滞。蛋白质合成抑制剂也可在WEHI-231细胞中诱导PCD，但在成熟B细胞系BAL-17中则不然。免疫抑制剂诱导的和蛋白质合成抑制剂诱导的PCD（而非生长停滞）可通过bcl-xL的过表达来预防，而用bcl-2转染则不影响PCD或细胞周期停滞。这些结果表明，bcl-2和bcl-xL可能控制部分独立的系统来抑制淋巴细胞中的PCD，并且B细胞和T细胞中的PCD可能受到不同的调节。
