Parallel induction of nitric oxide and tetrahydrobiopterin synthesis in alveolar macrophages

Background: Nitric oxide (NO) and an essential cofactor for both constituti ve and inducible NO synthase (NOS) activity, tetrahydrobiopterin (6R-L-eryt hro-1',2'-dihydroxypropyl -2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine; B H4), are thought to be important modulators of function in normal and infla med airways. However, the exact pathologic roles of NO and BH4 remain obscu re. Even less is known about the effects of cytokines on alveolar macrophag es. Objective: This study was designed to determine whether NO and BH4 are induced by cytokines in mouse alveolar macrophages and to investigate wheth er NO synthesis is affected by changes in intracellular BH4 levels in alveo lar macrophages. Methods: We compared the induction by lipopolysaccharide ( LPS), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF alpha) , and interleukin-2 (IL-2) of NO production and BH4 synthesis in alveolar m acrophages. To determine whether NO synthesis is affected by changes in int racellular BH4 levels in alveolar macrophages, we used inhibitors of BH4 bi osynthesis. Results: Activation of alveolar macrophages induced parallel in creases in NO and intracellular BH4 levels, although induction of the latte r appears to be somewhat more sensitive than that of the latter to diverse cytokines. Inducible NO production in alveolar macrophages was blocked by i nhibitors of BH4 biosynthesis. IL-2, an important component of the immunomo dulatory system, was only a weak activator of alveolar macrophages by itsel f but potently synergized with IFN-gamma to stimulate the production of bot h NO and BH4. Conclusion: Our results suggest that BH4 synthesis in alveola r macrophages is a potential target for therapeutic intervention in airway inflammatory diseases, such as asthma, cystic fibrosis, and acute bronchial infections whose pathology may be mediated by overproduction of NO. Copyri ght (C) 2001 S. Karger AG, Basel.