Second-messenger pathways involved in the regulation of survival in germinal-centre B cells and in Burkitt lymphoma lines.
Spontaneous apoptosis in germinal-centre (GC) B cells can be prevented by treatment with anti-immunoglobulin (Ig). By contrast, susceptible group-I Burkitt lymphoma (BL) cells can be driven to apoptosis by anti-Ig. The second-messenger pathways involved in the regulation of apoptosis in GC B lymphocytes and in BL cell lines were studied using pharmacological agonists or inhibitors of intracellular calcium ([Ca2+]i) and protein kinase C (PKC). Anti-Ig was found to mobilize Ca2+ in group-I cells. Pre-incubation with the Ca2+ chelator EGTA partially reduced apoptosis induced by anti-Ig or by Ca2+ ionophore in group-I BL cells. Activation of PKC with phorbol ester reduced such Ca(2+)-driven programmed cell death (PCD) to control levels of apoptosis. Apoptosis in group-I BL cell lines could also be triggered by the kinase inhibitors staurosporine and Ro-31-8220 at concentrations selective for PKC activity. Expression of the bcl-2 protein in BL group-I cells following gene transfer affords protection from apoptosis induced by ionomycin or anti-Ig. In the present study, bcl-2 was additionally found to protect from apoptosis driven by staurosporine. The high levels of spontaneous apoptosis exhibited by normal GC B cells were reduced, but not abrogated, by co-culture with phorbol ester. These results indicate that, in group-I BL cells, imbalance in the phosphoinositide pathway of signalling, in favour of [Ca2+]i and away from PKC, results in apoptosis: constitutive phosphorylation of key proteins by PKC may therefore suppress apoptosis in BL as well as in GC B cells.
Knox
K A
KA
Department of Immunology, University of Birmingham, UK.
Finney
M
M
Milner
A E
AE
Gregory
C D
CD
Wakelam
M J
MJ
Michell
R H
RH
Gordon
J
J
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D009857:Oncogenes / Q000235:genetics; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D010703:Phorbol Esters; D011493:Protein Kinase C; D002118:Calcium