Abstract
Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expression. In this study we show that BH4 availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-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 BH4 in the modulation of mesangial cell responses to pro-inflammatory stimuli.
Copyright 1997 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biopterins / analogs & derivatives*
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Biopterins / pharmacology
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Cells, Cultured
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Cyclooxygenase 2
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Dinoprostone / metabolism
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects*
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Glomerular Mesangium / enzymology*
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Humans
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Interleukin-1 / pharmacology
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Isoenzymes / biosynthesis*
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Membrane Proteins
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Methotrexate / pharmacology
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NG-Nitroarginine Methyl Ester / pharmacology
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Oxadiazoles / pharmacology
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Prostaglandin-Endoperoxide Synthases / biosynthesis*
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Pteridines / pharmacology*
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Pterins*
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Quinoxalines / pharmacology
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RNA, Messenger / biosynthesis
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Recombinant Proteins / pharmacology
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Transcription, Genetic / drug effects*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
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Enzyme Inhibitors
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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Oxadiazoles
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Pteridines
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Pterins
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Quinoxalines
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RNA, Messenger
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Biopterins
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sepiapterin
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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sapropterin
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Dinoprostone
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NG-Nitroarginine Methyl Ester
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Methotrexate