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Elevation of cytosolic calcium (Ca2+i) has been reported to induce apoptosis in a number of cell types. However, in the neutrophil, which undergoes apoptosis constitutively during aging in vitro, activation by inflammatory mediators elevates Ca2+i and prolongs lifespan via inhibition of apoptosis. To examine this paradox, we investigated the effects of modulation of Ca2+i upon apoptosis of neutrophils in vitro. Calcium ionophores (A23187, ionomycin) retarded apoptosis in neutrophil populations after 20 h (P < 0.001). Conversely, intracellular Ca(2+)-chelation, using bis-(o-aminophenoxy)-N,N,N'N'-tetraacetic acid (BAPTA) acetoxymethyl ester (AM) promoted apoptosis (P < 0.02). W-7 (an inhibitor of calmodulin) also promoted apoptosis (P < 0.05). Measurements of Ca2+i, using fura-2, showed (a) increased apoptosis in neutrophil populations was not associated with elevated Ca2+i, (b) neutrophils cultured with ionophore at concentrations inhibiting apoptosis exhibited transient (< 1 h) elevations of Ca2+i, to levels previously reported with receptor-mediated stimuli, and (c) BAPTA was able to prevent the elevation of Ca2+i and the inhibition of apoptosis produced by ionophore. Modulation of apoptosis occurred without alterations in intracellular pH. Thus, in the neutrophil, unlike lymphoid cells, elevation of Ca2+i exerts an inhibitory effect upon apoptosis. Furthermore, these data suggest that transient elevation of Ca2+i elicits signaling events leading to prolonged inhibition of apoptosis.
Whyte et al. (Thu,) studied this question.