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

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Abstract
Objective— Synthesis of tetrahydrobiopterin (BH 4 ), 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 BH 4 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 BH 4 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)-1β/tumor necrosis factor-α/interferon-γ, mainly through de novo transcription. On immunostimulation, PTPS became rate-limiting. Importantly, IL-1β induced PTPS rather than GTPCH. As a result, IL-1β contributed significantly to the amount of BH 4 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 BH 4 synthesis in cytokine-stimulated HCAECs and point to IL-1β as a leading cytokine in this process.