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The Journal of Immunology, 00, 165: 1782-1789.
Copyright © 00 by The American Association of Immunologists

Differential Role of p38 and c-Jun N-Terminal Kinase 1 Mitogen-Activated Protein Kinases in NK Cell Cytotoxicity1

Rossana Trotta, Katia Fettucciari, Livio Azzoni, Bekele Abebe, Kristin A. Puorro, Laurence C. Eisenlohr and Bice Perussia2

Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107

The serine-threonine mitogen-activated protein kinase (MAPK) family includes extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 kinases. In NK cells, spontaneous or Ab-mediated recognition of target cells leads to activation of an ERK-2 MAPK-dependent biochemical pathway(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. Our data indicate that p38 is activated in primary human NK cells upon stimulation with immune complexes and interaction with NK-sensitive target cells. Fc{gamma}RIIIA-induced granule exocytosis and both spontaneous and Ab-dependent cytotoxicity were reduced in a dose-dependent manner in cells pretreated with either of two specific inhibitors of this kinase. Target cell-induced IFN-{gamma} and Fc{gamma}RIIIA-induced TNF-{alpha} mRNA accumulation was similarly affected under the same conditions. Lack of inhibition of NK cell cytotoxicity in cells overexpressing an inactive form of JNK1 indicates that 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 cytotoxicity.




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