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.