Contribution of clonally distinct subpopulations to heterogeneous production of inducible nitric oxide synthase by LPS-stimulated mouse macrophages

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Abstract
Expression of the inducible nitric oxide synthase (iNOS) gene in mouse macrophages can be induced by bacterial lipopolysaccharide (LPS). iNOS (EC 1.14.13.39) catalyzes production of the reactive nitrogen intermediate, nitric oxide (NO), which is very important to macrophage-mediated host defense in species such as the mouse and rat. We have investigated production of iNOS at the level of single cells through immunocytochemical analysis of LPS-stimulated macrophages. Both bone marrow culture-derived macrophages and those of the cell line, RAW 264.7, were examined. Heterogeneous production of iNOS within macrophage populations was explained in part by the existence of clones that were high producers of iNOS and, therefore, NO, while other clones were reproducibly low producers of each. All clonally derived populations continued to demonstrate heterogeneous iNOS production, suggesting that at least one additional mechanism must be responsible for the phenomenon of heterogeneity. In contrast to iNOS, LPS-stimulated macrophages synthesized interferonβ (IFNβ) uniformly throughout the population.