The present study demonstrates that murine dermal fibroblasts produce nitrite (NO2-) and nitrate (NO3-) upon treatment with interferon gamma (IFN-gamma). This formation is dependent on L-arginine and can be inhibited by the L-arginine analogue NG-monomethyl-L-arginine. The effect of IFN-gamma is drastically increased by cotreatment with tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), or lipopolysaccharide (LPS). The tested cytokines also induce formation of tetrahydrobiopterin in murine fibroblasts. Inhibition of guanosine triphosphate-cyclohydrolase I, the key enzyme of tetrahydrobiopterin de novo synthesis with 2,4-diamino-6-hydroxy-pyrimidine, leads to decreased formation of NO2- and NO3-. This effect can be reversed by addition of sepiapterin, which provides tetrahydrobiopterin via a salvage pathway. Methotrexate, which inhibits the salvage pathway, blocks the restoration of NO2- and NO3- production by sepiapterin. The cytotoxic effect of combinations of IFN-alpha with TNF-gamma, IL-1, or LPS is attenuated by inhibition of tetrahydrobiopterin synthesis. These results show that intracellular concentrations of tetrahydrobiopterin control the amount of NO2- and NO3- produced in situ and suggest that the role of cytokine-induced tetrahydrobiopterin synthesis is to provide cells with the active cofactor for production of nitrogen oxides.
Article|
December 01 1990
Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts.
G Werner-Felmayer,
G Werner-Felmayer
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
E R Werner,
E R Werner
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
D Fuchs,
D Fuchs
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
A Hausen,
A Hausen
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
G Reibnegger,
G Reibnegger
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
H Wachter
H Wachter
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Search for other works by this author on:
G Werner-Felmayer
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
E R Werner
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
D Fuchs
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
A Hausen
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
G Reibnegger
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
H Wachter
Department of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1990) 172 (6): 1599–1607.
Citation
G Werner-Felmayer, E R Werner, D Fuchs, A Hausen, G Reibnegger, H Wachter; Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts.. J Exp Med 1 December 1990; 172 (6): 1599–1607. doi: https://doi.org/10.1084/jem.172.6.1599
Download citation file: