Interleukin 2 activates nuclear phospholipase Cß by mitogen-activated protein kinase-dependent phosphorylation in human natural killer cells

It is not yet clear whether nuclear phospholipase C (PLC) signaling is implicated in the response of primary cells to cytokines or not and, in particular, whether lymphocytes utilize the nuclear phosphoinositides breakdown as a step in the signal transduction generated by cytokine receptor triggering. Therefore, we have studied the repertoire and functional regulation of nuclear PLC, the key enzyme of phosphoinositides turnover, by interleukin-2 (IL-2) in primary human natural killer (NK) cells and its effects on the IL-2-driven NK cell proliferation. We found that 1) IL-2 stimulates nuclear PLC activity within 60 min of treatment; 2) NK cells express only the beta family of PLCs in the nucleus, and the isoform of this enzyme regulated by IL- 2 is PLC beta (1)b; 3) IL- 2 induces nuclear translocation of extracellular signal-related kinase (ERK)-2, or p42, and to a lesser extent, of ERK-1, or p44, of mitogen-activated protein kinase (MAPK), whose specific inhibition prevents the IL-2-driven nuclear PLC beta (1) activation; 4) PLC beta (1)b is serine-phosphorylated after IL- 2, and the phosphorylation is abolished after MAPK inhibition; and 5) inhibition of nuclear PLC activation leads to the inhibition of the IL-2-induced proliferation of NK cells. Altogether, our data indicate that nuclear PLC signaling is a downstream target of the ERK/MAPK pathway stimulated by IL-2 receptor triggering in human primary NK cells, and that the nuclear phosphoinositides turnover is a key step in proliferative response of NK cells to IL-2.