Early events in human B cell activation: metabolic pathways vary according to the first signal used

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Abstract
The effects of the calcium channel blocking drug Verapamil and of palmitoyl‐carnitin (PTC), an inhibitor of protein‐kinase C activity, on human B cell activation were measured. Both Verapamil and PTC inhibited the B cell proliferation induced by costimulation with anti‐μ antibody and with 3 different growth factors: interleukin 2, 20‐kDa B cell growth factor and 50‐kDa B cell growth factor. Both uridine and thymidine incorporation induced by costimulation with ionomycin and phorbol 12‐myristate 13‐acetate (PMA) were inhibited by Verapamil and PTC. In contrast, B cell proliferation was resistant to Verapamil (while being still inhibited by PTC) in two situations: (a) when B cells were costimulated with PMA and growth factors and (b) when B cells previously activated in vitro (by anti‐μ antibody or PMA) were stimulated with growth factors. These results confirm that the late stage (Gl → S transition) of B cell activation is independent of Ca2+ entry. More importantly, they show that the initial events induced by anti‐μ antibody and by PMA are based on different biochemical pathways: PMA would act on a subpopulation of B cells which has already received an early signal of activation in vivo. This emphasizes the functional and biochemical heterogeneity of the G0 stage among circulating B cells.