Genestier L, Dearden-Badet M T, Bonnefoy-Berard N, Lizard G, Revillard J P
Laboratoire d'immunologie, INSERM U80 UCBL, Hôpital E. Herriot, Lyon, France.
Cell Immunol. 1994 May;155(2):283-91. doi: 10.1006/cimm.1994.1122.
The WEHI-231 B lymphoma cell line expresses the phenotype of immature B cells. Cross-linking of surface IgM induces programmed cell death (PCD) with typical features of apoptosis demonstrated by the decrease of cell DNA content, chromatin condensation, and nuclear fragmentation. Activation of protein kinase C (PKC) by phorbol esters was reported to protect WEHI-231 cells against apoptosis induced by ligation of antigen receptors. It was therefore hypothesized that PCD could result from a defect in PKC response with an imbalance in the phosphoinositide pathway in favor of Ca2+ mobilization. In support of this hypothesis, we show here that apoptosis can be readily triggered by the calcium ionophore ionomycin. Furthermore, pretreatment of cells with cyclosporin A or FK506 which inhibit selectively the phosphoprotein calcineurin, a calcium-and calmodulin-dependent serine/threonine phosphatase, protects WEHI-231 cells against apoptosis induced by ionomycin or ligation of surface IgM. Unlike phorbol esters, cyclosporin A did not impair the rise of intracellular Ca2+ induced by cross-linking of antigen receptors. Altogether, the data indicate that the phosphorylation status of yet undefined key cellular substrates controls the cellular response to calcium-dependent apoptotic signals in this B cell lymphoma.
WEHI - 231 B淋巴瘤细胞系表达未成熟B细胞的表型。表面IgM的交联诱导程序性细胞死亡（PCD），其具有典型的凋亡特征，表现为细胞DNA含量减少、染色质凝聚和核碎裂。据报道，佛波酯激活蛋白激酶C（PKC）可保护WEHI - 231细胞免受抗原受体连接诱导的凋亡。因此，有人推测PCD可能是由于PKC反应缺陷以及磷酸肌醇途径失衡，有利于Ca2+动员所致。为支持这一假设，我们在此表明钙离子载体离子霉素可轻易引发凋亡。此外，用环孢素A或FK506预处理细胞，它们可选择性抑制磷酸蛋白钙调神经磷酸酶（一种钙和钙调蛋白依赖性丝氨酸/苏氨酸磷酸酶），可保护WEHI - 231细胞免受离子霉素或表面IgM连接诱导的凋亡。与佛波酯不同，环孢素A不会损害抗原受体交联诱导的细胞内Ca2+升高。总之，数据表明尚未明确的关键细胞底物的磷酸化状态控制着这种B细胞淋巴瘤中细胞对钙依赖性凋亡信号的反应。
