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The human lymphoma cell line NK-92 has many characteristics of human natural killer cells. We have examined NK-92 activation by a full panel of human alpha Interferons (IFNs) by measuring IFN gamma secretion. We confirmed that NK-92 cells secrete IFN gamma in response to IFN alpha 2 in a dose-dependent manner. The IFN gamma response is enhanced by addition of IL-2, IL-18 or PMA, as has been seen with human donor NK cells. The EC50 for IFN alpha 2 ranges between 700–3000 pg/ml. Inclusion of IL-18 exhibited little effect on IFN potency but significant enhancement of IFN efficacy. EC50 values differ by >1000 fold between the IFN subtypes. Alpha 1 demonstrated the weakest activity while alpha 10 and beta 1a were the most potent. The relative potency of the IFNs correlates well with ability to phosphorylate STAT1 and 2. When NK-92 potency is compared with antiviral activity on A549 cells and antiproliferative activity on OVCAR3 cells, there are subtle but significant differences in the rank orders of potency and potencies relative to IFN alpha 2. These studies will be extended to examination of donor NK cells, additional signal transduction pathways, and the secretion of other cyto/chemokines