Differential role of p38 and c-Jun N-terminal kinase 1 mitogen-activated protein kinases in NK cell cytotoxicity

The serine-threonine mitogen-activated protein kinase (MAPK) family include s extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (J NK), and p38 kinases. In NK cells, spontaneous or Ah-mediated recognition o f target cells leads to activation of an ERK-2 MAPK-dependent biochemical p athway(s) involved in the regulation of NK cell effector functions. Here we assessed the roles of p38 and JNK MAPK in NK cell-mediated cytotoxicity, O ur data indicate that p38 is activated in primary human NK cells upon stimu lation with immune complexes and interaction with NK-sensitive target cells . Fc gamma RIIIA-induced granule exocytosis and both spontaneous and Ab-dep endent cytotoxicity were reduced in a dose-dependent manner in cells pretre ated with either of two specific inhibitors of this kinase. Target cell-ind uced IFN-gamma and Fc gamma RIIIA-induced TNF-alpha mRNA accumulation was s imilarly affected under the same conditions. Lack of inhibition of NK cell cytotoxicity in cells overexpressing an inactive form of JNK1 indicates tha t this kinase, activated only upon Fc gamma RIIIA ligation, does not play a significant role in cytotoxicity, These data underscore the involvement of p38, but not JNK1, in the molecular mechanisms regulating NK cell cytotoxi city.