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Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2.
Cell Death Differ 1999; 6(5):445-53CD

Abstract

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.

Authors+Show Affiliations

INSERM U131, 32 rue des carnets, 92140 Clamart, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10381635

Citation

Schrantz, N, et al. "Manganese Induces Apoptosis of Human B Cells: Caspase-dependent Cell Death Blocked By Bcl-2." Cell Death and Differentiation, vol. 6, no. 5, 1999, pp. 445-53.
Schrantz N, Blanchard DA, Mitenne F, et al. Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. Cell Death Differ. 1999;6(5):445-53.
Schrantz, N., Blanchard, D. A., Mitenne, F., Auffredou, M. T., Vazquez, A., & Leca, G. (1999). Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. Cell Death and Differentiation, 6(5), pp. 445-53.
Schrantz N, et al. Manganese Induces Apoptosis of Human B Cells: Caspase-dependent Cell Death Blocked By Bcl-2. Cell Death Differ. 1999;6(5):445-53. PubMed PMID: 10381635.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. AU - Schrantz,N, AU - Blanchard,D A, AU - Mitenne,F, AU - Auffredou,M T, AU - Vazquez,A, AU - Leca,G, PY - 1999/6/25/pubmed PY - 1999/6/25/medline PY - 1999/6/25/entrez SP - 445 EP - 53 JF - Cell death and differentiation JO - Cell Death Differ. VL - 6 IS - 5 N2 - 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. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/10381635/Manganese_induces_apoptosis_of_human_B_cells:_caspase_dependent_cell_death_blocked_by_bcl_2_ L2 - http://dx.doi.org/10.1038/sj.cdd.4400508 DB - PRIME DP - Unbound Medicine ER -