The expression of
inducible nitric oxide synthase (iNOS) expression and release of
nitric oxide (NO) from macrophages are markedly increased in granulomatous
infections. Activation of macrophages 1alpha-hydroxylase results in an increase of
1alpha,25-dihydroxyvitamin D(3) [
1,25(OH)(2)D(3)]. However, the significance of this increased production is not completely understood. In this study, we analyzed
1,25(OH)(2)D(3) and NO production in patients with
tuberculosis infection and
hypercalcemia and used
lipopolysaccharide (LPS) to stimulate RAW 264.7 cells in an attempt to assess iNOS expression and gaseous NO production regulated by
1,25(OH)(2)D(3).
Peroxynitrite (OONO(-)) production and
lactate dehydrogenase activity were also examined. Without additional stimulation, peripheral-blood mononuclear cells (PBMCs) from patients with
tuberculosis converted more
25-hydroxyvitamin D(3) to
1,25(OH)(2)D(3) than did those from normal controls. These PBMCs released less NO than did those from control subjects, at baseline and in the stimulated state. We found that
1,25(OH)(2)D(3) dose-dependently inhibited iNOS
messenger RNA expression of the LPS-stimulated RAW 264.7 cells and also significantly reduced the gaseous NO release and OONO(-) production. Paralleling the 1,25(OH)(2)D(3)-induced inhibition of NO release were reductions in OONO(-) and LDH production. In conclusion,
1,25(OH)(2)D(3) inhibited iNOS expression and reduced NO production by LPS-stimulated macrophages in the range of physiological doses. Inhibition of the NO surge was coupled with a reduction in OONO(-) and LDH production. Increased
1,25(OH)(2)D(3) production and decreased release of NO from the PBMCs of patients with
tuberculosis and
hypercalcemia were also noted. We propose that
1,25(OH)(2)D(3) production by macrophages may protect themselves against oxidative injuries caused by the NO burst. In the case of
tuberculosis infection, increased
1,25(OH)(2)D(3) synthesis may further contribute to the development of an unwanted phenomenon-
hypercalcemia.