The phosphoprotein phosphatase calcineurin controls calcium-dependent apoptosis in B cell lines.
Group I Burkitt's lymphoma cell lines and the B104 lymphoma cell line which expresses a phenotype of immature B cells undergo apoptosis after cross-linking of their surface immunoglobulin (Ig) receptors or after exposure to a calcium ionophore, while protein kinase C (PKC)-activating phorbol esters prevent such apoptosis. We show here that blockade of the phosphoprotein phosphatase calcineurin or phosphatase 2B by cyclosporin A (CsA) also protects these B cell lines against Ca(2+)-dependent apoptosis but not against apoptosis triggered by the PKC inhibitor chelerythrine or by serum deprivation. Okadaic acid, an inhibitor of phosphatases 1, 2A and 2C was ineffective. Among a series of human cytokines tested, only interferon-alpha and tumor necrosis factor-alpha were shown to protect against Ca(2+)-dependent apoptosis when used alone or in combination with CsA. In contrast to phorbol esters which block the progression into the S/G2 phases of the cell cycle, CsA partially restored the proliferation of cells exposed to the calcium ionophore. Altogether these data provide indirect evidence for the control of B cell apoptosis by the serine/threonine phosphorylation status of yet undefined key cellular substrates.
Bonnefoy-Berard
N
N
Laboratoire d'Immunologie, INSERM U80 UCBL, Hôpital E. Herriot, Lyon, France.
Genestier
L
L
Flacher
M
M
Revillard
J P
JP
D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology*; D019703:Calcineurin; D002118:Calcium / Q000502:physiology; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D002148:Calmodulin-Binding Proteins; D007075:Immunoglobulin M; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D015759:Ionomycin; D016572:Cyclosporine; D011493:Protein Kinase C; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium