Biochemistry and function of pteridine synthesis in human and murine macrophages

We investigated intracellular pteridine concentrations, activities of pteridine biosynthetic enzymes and formation of nitrogen oxides from arginine in human peripheral-blood-derived macrophages and in myelomonocytoma (THP-1) cells, as well as in murine peritoneal and spleen-derived macrophages and in murine macrophage lines (P388-D1, J774-A.1). Interferon-gamma (IFN-gamma) induces the activity of GTP-cyclohydrolase I up to 40-fold in human cells. In human macrophages and THP-1 cells, this induced activity is higher than the constitutively present activity of the subsequent enzyme, the 6-pyruvoyltetrahydropterin synthase. As a consequence, large amounts of neopterin are formed during IFN-gamma-triggered synthesis of tetrahydrobiopterin. Murine macrophages constitutively synthesize tetrahydrobiopterin. The activity of GTP-cyclohydrolase I remains unchanged by treatment with IFN-gamma or tumor necrosis factor-alpha. This activity is lower than the subsequent 6-pyruvoyltetrahydropterin synthase activity, thus explaining the lack of neopterin in murine cells, tissues and body fluids. Inhibition and reconstitution of pteridine synthesis in activated murine macrophages by specific drugs demonstrate that tetrahydrobiopterin regulates the amount of nitrogen oxides formed from arginine in intact cells, thus providing a rationale for therapeutic intervention.