Schrantz N, Blanchard D A, Mitenne F, Auffredou M T, Vazquez A, Leca G
INSERM U131, 32 rue des carnets, 92140 Clamart, France.
Cell Death Differ. 1999 May;6(5):445-53. doi: 10.1038/sj.cdd.4400508.
Manganese ions block apoptosis of phagocytes induced by various agents. The prevention of apoptosis was attributed to the activation of manganous superoxide dismutase (Mn-SOD) and to the antioxidant function of free Mn2+ cations. However, the effect of Mn2+ on B cell apoptosis is not documented. In this study, we investigated the effects of Mn2+ on the apoptotic process in human B cells. We observed that Mn2+ but not Mg2+ or Ca2+, inhibited cell growth and induced apoptosis of activated tonsilar B cells, Epstein Barr virus (EBV)-negative Burkitt's lymphoma cell lines (BL-CL) and EBV-transformed B cell lines (EBV-BCL). In the same conditions, no apoptosis was observed in U937, a monoblastic cell line. Induction of B cell apoptosis by Mn2+ was time- and dose-dependent. The cell permeable tripeptide inhibitor of ICE family cysteine proteases, zVAD-fmk, suppressed Mn2+-induced apoptosis. Furthermore, Mn2+ triggered the activation of interleukin-1beta converting enzyme (ICE/caspase 1), followed by the activation of CPP32/Yama/Apopain/caspase-3. In addition, poly-(ADP-ribose) polymerase (PARP), a cellular substrate for CPP32 protease was degraded to generate apoptotic fragments in Mn2+-treated B cell lines. The inhibitor, zVAD-fmk suppressed Mn2+-triggered CPP32 activation and PARP cleavage and apoptosis. These results indicate that the activation of caspase family proteases is required for the apoptotic process induced by Mn2+ treatment of B cells. While the caspase-1 inhibitor YVAD was unable to block apoptosis, the caspase-3 specific inhibitor DEVD-cmk, partially inhibited Mn2+-induced CPP32 activation, PARP cleavage and apoptosis of cells. Moreover, Bcl-2 overexpression in BL-CL effectively protected cells from apoptosis and cell death induced by manganese. This is the first report showing the involvement of Mn2+ in the regulation of B lymphocyte death presumably via a caspase-dependent process with a death-protective effect of Bcl-2.
锰离子可阻止多种因素诱导的吞噬细胞凋亡。细胞凋亡的预防归因于锰超氧化物歧化酶（Mn-SOD）的激活以及游离Mn2+阳离子的抗氧化功能。然而，Mn2+对B细胞凋亡的影响尚无文献记载。在本研究中，我们调查了Mn2+对人B细胞凋亡过程的影响。我们观察到，Mn2+而非Mg2+或Ca2+，抑制活化的扁桃体B细胞、爱泼斯坦-巴尔病毒（EBV）阴性的伯基特淋巴瘤细胞系（BL-CL）和EBV转化的B细胞系（EBV-BCL）的细胞生长并诱导其凋亡。在相同条件下，单核细胞系U937未观察到凋亡。Mn2+诱导B细胞凋亡具有时间和剂量依赖性。ICE家族半胱氨酸蛋白酶的细胞可渗透三肽抑制剂zVAD-fmk可抑制Mn2+诱导的凋亡。此外，Mn2+触发白细胞介素-1β转化酶（ICE/半胱天冬酶1）的激活，随后激活CPP32/Yama/Apopain/半胱天冬酶-3。此外，聚（ADP-核糖）聚合酶（PARP），一种CPP32蛋白酶的细胞底物，在Mn2+处理的B细胞系中被降解以产生凋亡片段。抑制剂zVAD-fmk抑制Mn2+触发的CPP32激活、PARP裂解和凋亡。这些结果表明，半胱天冬酶家族蛋白酶的激活是Mn2+处理B细胞诱导凋亡过程所必需的。虽然半胱天冬酶-1抑制剂YVAD无法阻断凋亡，但半胱天冬酶-3特异性抑制剂DEVD-cmk可部分抑制Mn2+诱导的CPP32激活、PARP裂解和细胞凋亡。此外，BL-CL中Bcl-2的过表达有效地保护细胞免受锰诱导的凋亡和细胞死亡。这是首次报道表明Mn2+可能通过半胱天冬酶依赖性过程参与B淋巴细胞死亡的调控，且Bcl-2具有死亡保护作用。
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