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Abstract
Nitric oxide (NO) is synthesised by many cell types involved in immunity and inflammation.
The principal enzyme involved is the inducible type-2 isoform of nitric oxide synthase
(NOS-2), which produces high-level sustained NO synthesis. NO is important as a toxic
defense molecule against infectious organisms. It also regulates the functional activity,
growth and death of many immune and inflammatory cell types including macrophages,
T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer
cells. However, the role of NO in nonspecific and specific immunity in vivo and in
immunologically mediated diseases and inflammation is poorly understood. NO does not
act through a receptor-its target cell specificity depends on its concentration, its
chemical reactivity, the vicinity of target cells and the way that target cells are
programmed to respond. At high concentrations as generated by NOS-2, NO is rapidly
oxidised to reactive nitrogen oxide species (RNOS) that mediate most of the immunological
effects of NOS-2-derived NO. RNOS can S-nitrosate thiols to modify key signalling
molecules such as kinases and transcription factors. Several key enzymes in mitochondrial
respiration are also inhibited by RNOS and this leads to a depletion of ATP and cellular
energy. A combination of these interactions may explain the multiple actions of NO
in the regulation of immune and inflammatory cells.