Availability of tetrahydrobiopterin is not a factor in the inability to detect nitric oxide production by human macrophages.

Human macrophages, in contrast to murine macrophages, do not produce nitric oxide after stimulation with cytokines. This failure has been attributed to the known lack of production by human macrophages of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase. Increasing intracellular levels of tetrahydrobiopterin in cytokine-stimulated murine cells results in an increase in nitrite production. However, this treatment does not result in any detectable accumulation of nitrite by stimulated human monocyte-derived macrophages. Thus, the inability of these cells to produce nitric oxide appears to be unrelated to a lack of tetrahydrobiopterin and suggests that proper in vitro conditions may not yet have been discovered that permit nitric oxide synthesis by activated human macrophages.