Regulation of p38 mitogen-activated protein kinase during NK cell activation

The mitogen-activated protein kinase (MAPK) p38 modulates a variety of cell ular functions, including proliferation, differentiation and cell death. Ho wever, we report here a novel function for p38, i.e. the regulation of cyto toxic lymphocyte-mediated cytotoxicity. Stimulation of NK cells by either c ross-linking of their Fc gamma RIII receptors or by binding to NK-sensitive target cells induces the phosphorylation and activation of p38, and also o f its upstream regulators MKK3/MKK6. Pharmacologic analyses suggest that Sr c-family and Syk-family protein tyrosine kinases couple the NK cell surface receptors to p38 activation. The role of p38 in the cytotoxic function of NK cells was tested by treatment of NK cells with the cell-permeable, p38-s pecific inhibitor SB203580. Interestingly, exposure to the drug reduced bot h antibody dependent cellular cytotoxicity and natural cytotoxicity, but ma ximal inhibitory concentrations resulted in only partial inhibition. Collec tively, these results suggest that the p38 MAPK pathway is stimulated durin g the development of NK cell-mediated cytotoxicity and that efficient killi ng is influenced by both p38-dependent and p38-independent pathways. More b roadly, this study identifies the regulation of cell-mediated killing as a novel role for p38 in cytotoxic lymphocytes.