INVOLVEMENT OF NITRIC-OXIDE SYNTHASE IN ANTIPROLIFERATIVE ACTIVITY OFMACROPHAGES - INDUCTION OF THE ENZYME REQUIRES 2 DIFFERENT KINDS OF SIGNAL ACTING SYNERGISTICALLY

Activated rodent macrophages inhibit micro-organism and tumour cell gr owth through a high output of nitric oxide; generated by an isoform of nitric oxide synthase which is induced, for example, in murine macrop hages, by concomitant stimulation with interferon-gamma (IFN-gamma) an d 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 s ynthesis required either simultaneous or sequential exposure to IFN-ga mma 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 disting uished: 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 ge ne.