Cytokines involved in the augmentation of murine natural killer cell activity by pyrimidinones in vivo.

Therapeutically active pyrimidinones such as 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP, Bropirimine) are known to be potent immuno-modulators. This includes their ability to markedly augment murine natural killer (NK) cell activity as measured in ex vivo NK assays. We now report the use of a murine in vivo NK assay, based on the rate of NK-cell mediated clearance of radiolabeled tumor cells from the lungs, to directly demonstrate in vivo NK augmentation by several pyrimidinones, including ABPP. In order to evaluate the involvement of the cytokines interferon (IFN), interleukin-1 (IL-1), and interleukin-2 (IL-2) in ABPP-induced NK augmentation, we first showed that injection of purified IFN or IL-1, but not IL-2, resulted in significant enhancement of in vivo NK activity. However, the mixture of IFN, IL-1, and IL-2 synergistically enhanced NK activity more than with any of the cytokines alone. We then showed that ABPP induced significant serum levels of IFN and IL-1, but not IL-2. The induction of IL-1 by ABPP in vivo was further verified by demonstration of increased serum levels of the acute phase protein serum amyloid P in ABPP-treated mice. The possible induction of IL-2 by ABPP was further investigated by using cyclosporin A (CsA) to inhibit IL-2 production in vivo. No diminution of ABPP-induced NK augmentation was seen, however, in CsA treated mice. These results suggest a role for IFN and IL-1 in the augmentation of NK activity in vivo by ABPP, but no evidence for a role for IL-2 was found.