Natural Killer Cell Cytotoxitcity is Dependent upon the MAP Kinases p38 and ERK
Boos, Markus D.
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Natural killer (NK) cells represent a unique hematopoietic lineage in their ability to destroy tumors and virally infected cells without prior sensitization, yet details of the dual forms of NK cytotoxicity (antibody-dependent and natural cytotoxicity) remain poorly characterized. Extracellular signal related kinase (ERK) is a member of the mitogen activated protein (MAP) kinase family of enzymes that has been shown to be a necessary component of the signal cascades employed during the NK cytotoxic response. Like ERK, p38 is another MAP kinase that has been shown to regulate immune responses in assorted hematopoietic cell lines and thus also has the potential to influence NK activation. In order to test whether p38 and ERK are necessary regulators ofNK cytotoxicity, NK cells were stimulated with both free antibody and target cells, after which biochemical and functional analyses were performed. Increased MAP kinase phosphorylation after NK stimulation suggested that ERK. and p38 are involved in signal transduction associated with NK cytotoxicity. This was further supported by evidence demonstrating that NK killing decreased following selective inhibition of either kinase. Also vital to the understanding of NK cells and the role of MAP kinases in NK-mediated immunity is knowledge of upstream regulators in the biochemical pathway whose function couples surface receptor stimulation to kinase activation. Using gene transfer techniques, it was observed that the guanosine-triphosphate (GTP) binding proteins rac and rho regulate p38 and ERK in the antibody-dependent NK cytotoxic signal pathway. Experimental results reinforce previous findings concerning ERK and support the hypothesis that p38 critically influences NK cell-mediated cytotoxicity. By incorporating this information into existing knowledge of NK signal transduction and function, it will be possible to develop pharmacological strategies that increase NK activation, leading to a greater therapeutic role for the cells in the treatment of cancer and infection.