Tetrahydrobiopterin modulates cyclooxygenase-2 expression in human mesangial cells.
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.
Pérez-Sala
D
D
Instituto "Reina Sofía" de Investigaciones Nefrológicas, C.S.I.C., Velázquez 144, Madrid, 28006, Spain. lperezsala@fresno.csic.es
Díaz-Cazorla
M
M
Ros
J
J
Jiménez
W
W
Lamas
S
S
D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005920:Glomerular Mesangium / Q000201:enzymology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D008727:Methotrexate / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011621:Pteridines / Q000494:pharmacology*; D011622:Pterins; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D010069:Oxadiazoles; D011621:Pteridines; D011622:Pterins; D011810:Quinoxalines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D001708:Biopterins; C016727:sepiapterin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C003402:sapropterin; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D008727:Methotrexate