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IL-18 and CD28 Use Distinct Molecular Mechanisms to Enhance NK Cell Production of IL-12-Induced IFN-¹

William Walker^*, Miguel Aste-Amezaga, Robert A. Kastelein, Giorgio Trinchieri and Christopher A. Hunter^2,*

^* Department of Pathobiology, University of Pennsylvania, and The Wistar Institute, Philadelphia, PA 19104; and Department of Molecular Biology, DNAX Research Institute, Palo Alto, CA 94304

NK cells play an important role in innate immune resistance, particularly through synthesis of the pro-inflammatory cytokine IFN-. This study compares the abilities of the cytokine IL-18 and the costimulatory cell surface molecule CD28 to enhance IL-12-driven IFN- production by NK cells. Studies with other cytokines (IL-1ß, IL-6, TNF-, IL-15) showed that IL-18 or anti-CD28 treatments were the most efficient inducers of IFN- when combined with IL-12. The ability of IL-18 to enhance IFN- was shown to be dependent on the presence of IL-12. Similarly, although anti-CD28 stimulation alone could enhance IFN- synthesis, this effect was significantly increased in the presence of IL-12. Although neither method of costimulation required de novo protein synthesis for their effects on IFN- mRNA expression, these molecules used distinct mechanisms. Specifically, nuclear run-on analysis revealed that IL-18 in combination with IL-12 enhanced the rate of transcription of the IFN- gene. Conversely, treatment with anti-CD28 plus IL-12 did not significantly up-regulate the rate of transcription of the IFN- gene, but stabilized IFN- mRNA expression within NK cells. These findings illustrate costimulatory pathways that result in potent IFN- responses by NK cells and show that although IL-18 and anti-CD28 can enhance the synthesis of IL-12-driven IFN-, they employ molecular mechanisms that are distinct from one another.

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