Involvement of nitric oxide synthase in antiproliferative activity of macrophages: induction of the enzyme requires two different kinds of signal acting synergistically

Abstract

Activated rodent macrophages inhibit micro-organism and tumour cell growth through a high output of nitric oxide; generated by an isoform of nitric oxide synthase which is induced, for example, in murine macrophages, by concomitant stimulation with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). We show here that LPS could be replaced as a co-stimulant by the mycobacterial derivative muramyl dipeptide (MDP) in macrophages, and by interleukin-1 (IL-1) in EMT-6 adenocarcinoma cells. Moreover, our results indicate that nitric oxide synthase RNA synthesis required either simultaneous or sequential exposure to IFN-gamma and MDP/IL-1; whereas exposure to MDP/IL-1 followed by exposure to IFN-gamma was ineffective. Thus, two kinds of signal could be distinguished: IFN-gamma on the one hand, acting first in an irreversible way, and LPS, MDP, IL-1 on the other hand, which seemed to be permanently required for continuous transcription of the nitric oxide synthase gene.