IL-12 and IL-15 induce activation of nuclear PLC_ in human natural killer cells

Nuclear phosphoinositide breakdown mediated by nuclear PLCbeta phosphorylation is a downstream effect of IL-2 stimulation in primary human NK cells that is involved in the proliferative response to IL-2. Here we investigated whether the nuclear phosphoinositide turnover in NK cells is a response confined to IL-2, or rather represents a more general mechanism of nuclear signalling linked to the proliferative response of NK cells to activatory cytokines. We therefore focused on IL-12 and IL-15- induced nuclear events in primary human NK cells. Our results show that IL- 12 and IL-15 activate nuclear PLCbeta1 in NK cells, with delayed kinetics as compared to IL-2. The nuclear PLC activation induced by the cytokines could be blocked by the MEK-1 inhibitor PD 98059, suggesting its dependence upon MAPKinase activation. Our conclusion is that the three cytokines that activate NK cells and that bind partially similar (IL-2, IL- 15) or different surface receptors (IL-12), all induce activation of PLCbeta1 in the nucleus of NK cells via MAPKinase. Thus, the activation of nuclear PLCbeta1 appears as a physiologically relevant general mechanism of response to cytokine stimulation in human natural killer cells.