Inducible nitric oxide synthase of macrophages. Present knowledge and evidence for species-specific regulation

Abstract

An important mechanism by which macrophages (M phi) halt the growth of and eliminate a broad array of intracellular pathogens is the production of nitric oxide (NO). NO generation is catalyzed by inducible nitric oxide synthase (iNOS) converting arginine into citrulline and NO. In murine M phi, iNOS activity is regulated largely at the transcriptional level. LPS and IFN-gamma induce iNOS, IL-4 and TGF-beta down-regulate LPS or IFN-gamma induced iNOS. In human M phi, iNOS cannot be induced by conventional activating regimes in vitro. We studied iNOS induction in ruminant monocytes and M phi from various sources (bone marrow, alveolar lavage, peripheral blood) and found that there is a species-specific and differentiation stage-dependent pattern of iNOS regulation in vitro. Notably, cattle M phi and monocytes respond to distinct signals by iNOS expression. Goat monocytes and M phi resemble human, pig and rabbit M phi in that upon treatment with conventional activating stimuli, they express less iNOS than unstimulated murine or bovine M phi and fail to generate detectable amounts of nitrite and nitrate.