MODULATION OF NITRIC-OXIDE SYNTHASE ACTIVITY IN MACROPHAGES

L-ARGININE is converted to the highly reactive and unstable nitric oxi de (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS ). NO decomposes into other nitrogen oxides such as nitrite (NO2-) and nitrate (NO3-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO-). Activated rodent macrophages a re capable of expressing an inducible form of this enzyme (iNOS) in re sponse to appropriate stimuli, i.e., lipopolysaccharide <LPS) and inte rferon-gamma (IFN gamma). Other cytokines can modulate the induction o f NO biosynthesis in macrophages. NO is a major effector molecule of t he anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthe sizing pathway has been demonstrated in human monocytes and other cell s, but its role in host defence seems to be accessory. A delicate func tional balance between microbial stimuli, host-derived cytokines and h ormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulat ion of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage.