Tetrahydrobiopterin Modulates Cyclooxygenase-2 Expression in Human Mesangial Cells

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4is also a limiting factor for NOS2 expression. In this study...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1997-12, Vol.241 (1), p.7-12
Main Authors: Pérez-Sala, Dolores, Dı́az-Cazorla, Manuela, Ros, Josefa, Jiménez, Wladimiro, Lamas, Santiago
Format: Article
Language:English
Subjects:
Biopterins - analogs & derivatives
Biopterins - pharmacology
Cells, Cultured
Cyclooxygenase 2
Dinoprostone - metabolism
Drug Synergism
Enzyme Inhibitors - pharmacology
Gene Expression Regulation, Enzymologic - drug effects
Glomerular Mesangium - enzymology
Humans
Interleukin-1 - pharmacology
Isoenzymes - biosynthesis
Membrane Proteins
Methotrexate - pharmacology
NG-Nitroarginine Methyl Ester - pharmacology
Oxadiazoles - pharmacology
Prostaglandin-Endoperoxide Synthases - biosynthesis
Pteridines - pharmacology
Pterins
Quinoxalines - pharmacology
Recombinant Proteins - pharmacology
RNA, Messenger - biosynthesis
Transcription, Genetic - drug effects
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4is also a limiting factor for NOS2 expression. In this study we show that BH4availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4donor sepiapterin potentiated IL-1β/TNF-α-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrates, an early event which occurred well before the induction of NOS2 could be evidenced. These findings suggest a role for BH4in the modulation of mesangial cell responses to pro-inflammatory stimuli.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1997.7761