Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Werner-Felmayer, G; Werner, ER; Fuchs, D; Hausen, A; Reibnegger, G; Wachter, H.
Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts.
J Exp Med. 1990; 172(6):1599-1607
Doi: 10.1084/jem.172.6.1599
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- Co-Autor*innen der Med Uni Graz
- Reibnegger Gilbert
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Biopterin - analogs and derivatives
- Cells, Cultured - analogs and derivatives
- Cytokines - pharmacology
- Fibroblasts - drug effects
- Interferon-gamma, Recombinant - pharmacology
- Interleukin-1 - pharmacology
- Kinetics - pharmacology
- Methotrexate - pharmacology
- Mice - pharmacology
- Mice, Inbred BALB C - pharmacology
- Nitrates - metabolism
- Nitrites - metabolism
- Pteridines - pharmacology
- Pterins - pharmacology
- Recombinant Proteins - pharmacology
- Skin - drug effects
- Sugar Acids - pharmacology
- Tumor Necrosis Factor-alpha - pharmacology