Acid-dependent dismutation of nitrogen oxides may be a critical source of nitric oxide in human macrophages

Abstract

The cytotoxic activity of the macrophage relies greatly on the secretion of a number of reactant intermediates, including superoxide (O2–), hydroxyl radical (OH–) and nitric oxide (NO). The latter, synthesized via cytokine-mediated induction of inducible NO-synthase (iNOS), is readily observed in murine macrophages. However, a poorly reproducible or minimal response to cytokine-stimulation in the human macrophage has questioned the presence or significance of this important pathway in man. Nevertheless, iNOS is present in other human phagocytic cells, e.g. neutrophils, while the NO metabolites, nitrite (NO2–) and nitrate (NO3–), are raised in human serum during infection. Low phagolysosomal pH is critical for the macrophage to destroy the engulfed pathogen. This acidic environment may allow synthesis of NO independently of iNOS via dismutation of NO2–to NO. Should this mechanism be active, assay for iNOS and NO by determination of NO2–could be misleading. In human macrophages, acid-induced conversion of imported nitrogen oxides (NOx) may take precedence over iNOS-mediated NO synthesis and should be investigated as a source of NO in these cells.