title: cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
abstract: We studied the effects of cAMP on cytokine (interferon-gamma plus tumor necrosis factor-alpha)-induced stimulation of tetrahydrobiopterin (BH4) synthesis in human umbilical vein endothelial cells (HUVEC). The cytokine mixture caused a marked increase in the biosynthesis and release of BH4 by HUVEC. Dibutyryl-cAMP produced a dose-dependent inhibition of this cytokine-induced stimulation of synthesis and release of BH4 by these cells. 8-Bromo-cAMP also caused a significant inhibition, although the effects were less marked than those of dibutyryl-cAMP. Both forskolin and the stable analog of prostacyclin, iloprost, caused cAMP accumulation and a concomitant diminution of the cytokine-induced BH4 synthesis in HUVEC. Dibutyryl-cAMP and iloprost also significantly inhibited the cytokine-induced stimulation of GTP cyclohydrolase I (GCHI) activity and mRNA production. We concluded that the suppression by the cAMP messenger system of cytokine-induced stimulation of synthesis and release of BH4 by HUVEC can be attributed to the inhibition of the activity of GCHI, the rate-limiting enzyme in BH4 biosynthetic pathway, in HUVEC. The data also suggest that the cAMP-mediated reduction in the GCHI mRNA level may at least partially explain the decline in GCHI activity. It is reasoned that under inflammatory conditions, cAMP-elevating agents such as prostacyclin exert regulatory effects on circulation by inhibiting cytokine-induced synthesis and release of BH4 by HUVEC.
authors: Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors: Masatsugu
authors: M
authors: Ohtsuki
authors: Hiroaki
authors: H
authors: Shiraishi
authors: Taiya
authors: T
authors: Kato
authors: Risa
authors: R
authors: Kuroda
authors: Masahiro
authors: M
authors: Tazawa
authors: Chiho
authors: C
authors: Sumi-Ichinose
authors: Shin
authors: S
authors: Tada
authors: Yasutoshi
authors: Y
authors: Udagawa
authors: Mitsuyasu
authors: M
authors: Itoh
authors: Hitoshi
authors: H
authors: Hishida
authors: Hiroshi
authors: H
authors: Ichinose
authors: Toshiharu
authors: T
authors: Nagatsu
authors: Yasumichi
authors: Y
authors: Hagino
authors: Takahide
authors: T
authors: Nomura
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
chemical_list: D004338:Drug Combinations; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D001708:Biopterins; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D007371:Interferon-gamma; D000242:Cyclic AMP; D006136:GTP Cyclohydrolase; C003402:sapropterin; D016285:Iloprost