Induction of tetrahydrobiopterin synthesis in human umbilical vein smooth muscle cells by inflammatory stimuli

Tetrahydrobiopterin (BH 4) is an obligatory cofactor and regulator of nitric oxide synthases (NOS). We evaluated the biosynthesis of BH 4 in human umbilical vein smooth muscle cells (HUVSMC). Trace amounts of BH 4 were found intra- and extracellularly in untreated cells. When HUVSMC were activated b...

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Bibliographic Details
Published in:Immunology letters 1998, Vol.60 (1), p.13-17
Main Authors: Walter, Roland, Linscheid, Philippe, Blau, Nenad, Kierat, Lucja, Schaffner, Andreas, Schoedon, Gabriele
Format: Article
Language:English
Subjects:
Biopterins - analogs & derivatives
Biopterins - biosynthesis
Cells, Cultured
Cytokines
Gene Expression
GTP Cyclohydrolase - genetics
Human
Humans
Inflammation
Interferon-gamma - pharmacology
Interleukin-1 - pharmacology
Lipopolysaccharides - pharmacology
Muscle, Smooth, Vascular - metabolism
Neopterin - metabolism
Nitric oxide
Polymerase Chain Reaction
Smooth muscle
Tetrahydrobiopterin
Tumor Necrosis Factor-alpha - pharmacology
Umbilical Veins - metabolism
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Summary:Tetrahydrobiopterin (BH 4) is an obligatory cofactor and regulator of nitric oxide synthases (NOS). We evaluated the biosynthesis of BH 4 in human umbilical vein smooth muscle cells (HUVSMC). Trace amounts of BH 4 were found intra- and extracellularly in untreated cells. When HUVSMC were activated by individual inflammatory stimuli (IL-1 β, TNF α, IFN γ or LPS), both intra- and extracellular levels of BH 4 increased significantly, with TNF α being the most potent single stimulus. Combined inflammatory cytokines synergized in the induction of an up to 600-fold increase of BH 4 synthesis. Addition of LPS to the cytokine mixture led to a further increase of BH 4 synthesis. Neopterin, a product of the first intermediate in BH 4 biosynthesis, was also raised, but to a much lesser extent. The increase of BH 4 synthesis was paralleled by an enhanced expression of isoform-1 (the only isoform coding for the active enzyme) of GTP cyclohydrolase I in cytokine treated cells. Our results show for the first time that BH 4 biosynthesis is strongly induced by combinations of inflammatory stimuli in HUVSMC. The importance of BH 4-dependent NO synthesis in HUVSMC needs, however, additional detailed studies.
ISSN:0165-2478
1879-0542
DOI:10.1016/S0165-2478(97)00123-5