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 (μ) antibodies leads to B cell activation resulting in numerous early biochemical events including an increase in intracellular [Ca²⁺]. Furthermore, anti‐μ‐activated B cells become able to proliferate in response to interleukin (IL)2 and IL 4. These studies examined the effect of the calcium ionophore ionomycin, an enhancer of cytoplasmic [Ca²⁺] levels, on IL 2 and IL 4‐mediated proliferation of anti‐μ‐stimulated normal human B cells. Ionomycin inhibited the proliferative response of anti‐μ‐activated B cells to IL 4. In contrast, IL 2 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‐μ‐costimulated B cells. Interestingly, in contrast to PBu₂, IL 4 did not prevent ionmycin‐dependent DNA fragmentation. Importantly, H7, an inhibitor of protein kinase C activation, down‐regulated only the IL 2 and PBu₂‐driven B cell proliferation but not B cell proliferative response to IL 4. These results suggest that putative protein kinase C activation, either by direct treatment with phorbol ester or during IL 2 signaling, counteracts the inhibitory effects of ionomycin. In contrast, IL 4 signaling does not exhibit the same protective properties.