Differential inhibition of interleukin 2- and interleukin 4-mediated human B cell proliferation by ionomycin: a possible regulatory role for apoptosis

Surface immunoglobulin (Ig) cross-linking by anti-IgM (mu) antibodies leads to B cell activation resulting in numerous early biochemical events including an increase in intracellular Ca2+]. Furthermore, anti-mu-activated B cells become able to proliferate in response to interleukin (IL)2 and IL4. These studies examined the effect of the calcium ionophore ionomycin, an enhancer of cytoplasmic Ca2+] levels, on IL2 and IL4-mediated proliferation of anti-mu-stimulated normal human B cells. Ionomycin inhibited the proliferative response of anti-mu-activated B cells to IL4. In contrast, IL2 and phorbol 12,13 dibutyrate (PBu2)-mediated B cell proliferation was refractory to the growth inhibitory effects of ionomycin. In an attempt to delineate a possible mechanism(s) for this differential growth effect of ionomycin, we first studied direct effects of ionomycin on activated B cells. Our data suggested that ionomycin induced DNA fragmentation in anti-mu-costimulated B cells. Interestingly, in contrast to PBu2, IL4 did not prevent ionomycin-dependent DNA fragmentation. Importantly, H7, an inhibitor of protein kinase C activation, down-regulated only the IL2 and PBu2-driven B cell proliferation but not B cell proliferative response to IL4. These results suggest that putative protein kinase C activation, either by direct treatment with phorbol ester or during IL2 signaling, counteracts the inhibitory effects of ionomycin. In contrast, IL4 signaling does not exhibit the same protective properties.