Critical Role of Interleukin-1 for Transcriptional Regulation of Endothelial 6-Pyruvoyltetrahydropterin Synthase

Objective—Synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases, is strongly induced on immunostimulation in vascular endothelial cells (VECs). Expression of GTP cyclohydrolase I (GTPCH), the first enzyme in BH4 biosynthesis, is regulated by cytokines and considered rate-limiting. Herein we investigated the molecular mechanism and relevance of cytokine-dependent regulation of 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme in BH4 synthesis, in human coronary artery endothelial cells (HCAECs). Methods and Results—Real-time polymerase chain reaction revealed a 4-fold induction of PTPS and a 300-fold induction of GTPCH expression by interleukin (IL)-1 /tumor necrosis factor/interferon, mainly through de novo transcription. On immunostimulation, PTPS became rate-limiting. Importantly, IL-1 induced PTPS rather than GTPCH. As a result, IL-1 contributed significantly to the amount of BH4 produced ( 40%) but concomitantly reduced the accumulation of the GTPCH intermediate, 7,8-dihydroneopterin triphosphate ( 50%). Conclusion—Our data show that PTPS induction is necessary for optimized BH4 synthesis in cytokine-stimulated HCAECs and point to IL-1 as a leading cytokine in this process. (Arterioscler Thromb Vasc Biol. 2003;23:●●●●●●.)