IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12

IFN-gamma a product of NK and T cells, is a key cytokine contributing innat e and adaptive immunity. IFN-gamma production is induced via direct cell-ce ll contacts with APC and IFN-gamma -producing cells or by cytokines, During microbial infections macrophage-derived IFN-alpha, IL-12, and IL-18 enhanc e IFN-gamma production and Th1 response Here we show that IFN-a in combinat ion with IL-18 very efficiently induces IFN-gamma expression also in primar y, nonactivated NK cells and in. NK-92 cell line. Comparison of the kinetic s of IFN-gamma mRNA expression in nonactivated NK cells, NK-92 cells and ac tivated T cells stimulated with IFN-alpha or IL-12 revealed that, although both of these cytokines directly up-regulate IFN-gamma mRNA expression, its levels remain elevated much longer with IL-12 stimulation. in both NK cell s and T cells, Stat4 is known to be critical in IL-12 and IFN-alpha signali ng. We show that Stat4 activation is transient in cells: stimulated with IF N-cc, whereas IL-12 induces more long-lasting activation of the transcripti on factor. This prolonged activation of IFN-gamma gene by IL-12 may result in more efficient IFN-gamma production. compared: to that of IFN-alpha. Our results demonstrate that IFN-alpha and IL-48 are important innate cytokine s in inducing NK cell. IFN-gamma production.