cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells

Masatsugu Ohtsuki, Hiroaki Shiraishi, Taiya Kato, Risa Kuroda, Masahiro Tazawa, Chiho Ichinose, Shin Tada, Yasutoshi Udagawa, Mitsuyasu Itoh, Hitoshi Hishida, Hiroshi Ichinose, Toshiharu Nagatsu, Yasumichi Hagino, Takahide Nomura

Research output: Contribution to journalArticle

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Abstract

We studied the effects of cAMP on cytokine (interferon-γ plus tumor necrosis factor-α)-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.

Original languageEnglish
Pages (from-to)2187-2198
Number of pages12
JournalLife Sciences
Volume70
Issue number18
DOIs
Publication statusPublished - 22-03-2002

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Biosynthesis
Endothelial cells
Human Umbilical Vein Endothelial Cells
GTP Cyclohydrolase
Cytokines
Iloprost
Epoprostenol
8-Bromo Cyclic Adenosine Monophosphate
Messenger RNA
Biosynthetic Pathways
Colforsin
sapropterin
Interferons
Tumor Necrosis Factor-alpha
Enzymes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Ohtsuki, Masatsugu ; Shiraishi, Hiroaki ; Kato, Taiya ; Kuroda, Risa ; Tazawa, Masahiro ; Ichinose, Chiho ; Tada, Shin ; Udagawa, Yasutoshi ; Itoh, Mitsuyasu ; Hishida, Hitoshi ; Ichinose, Hiroshi ; Nagatsu, Toshiharu ; Hagino, Yasumichi ; Nomura, Takahide. / cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. In: Life Sciences. 2002 ; Vol. 70, No. 18. pp. 2187-2198.
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abstract = "We studied the effects of cAMP on cytokine (interferon-γ plus tumor necrosis factor-α)-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.",
author = "Masatsugu Ohtsuki and Hiroaki Shiraishi and Taiya Kato and Risa Kuroda and Masahiro Tazawa and Chiho Ichinose and Shin Tada and Yasutoshi Udagawa and Mitsuyasu Itoh and Hitoshi Hishida and Hiroshi Ichinose and Toshiharu Nagatsu and Yasumichi Hagino and Takahide Nomura",
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Ohtsuki, M, Shiraishi, H, Kato, T, Kuroda, R, Tazawa, M, Ichinose, C, Tada, S, Udagawa, Y, Itoh, M, Hishida, H, Ichinose, H, Nagatsu, T, Hagino, Y & Nomura, T 2002, 'cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells', Life Sciences, vol. 70, no. 18, pp. 2187-2198. https://doi.org/10.1016/S0024-3205(02)01503-5

cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. / Ohtsuki, Masatsugu; Shiraishi, Hiroaki; Kato, Taiya; Kuroda, Risa; Tazawa, Masahiro; Ichinose, Chiho; Tada, Shin; Udagawa, Yasutoshi; Itoh, Mitsuyasu; Hishida, Hitoshi; Ichinose, Hiroshi; Nagatsu, Toshiharu; Hagino, Yasumichi; Nomura, Takahide.

In: Life Sciences, Vol. 70, No. 18, 22.03.2002, p. 2187-2198.

Research output: Contribution to journalArticle

TY - JOUR

T1 - cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells

AU - Ohtsuki, Masatsugu

AU - Shiraishi, Hiroaki

AU - Kato, Taiya

AU - Kuroda, Risa

AU - Tazawa, Masahiro

AU - Ichinose, Chiho

AU - Tada, Shin

AU - Udagawa, Yasutoshi

AU - Itoh, Mitsuyasu

AU - Hishida, Hitoshi

AU - Ichinose, Hiroshi

AU - Nagatsu, Toshiharu

AU - Hagino, Yasumichi

AU - Nomura, Takahide

PY - 2002/3/22

Y1 - 2002/3/22

N2 - We studied the effects of cAMP on cytokine (interferon-γ plus tumor necrosis factor-α)-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.

AB - We studied the effects of cAMP on cytokine (interferon-γ plus tumor necrosis factor-α)-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.

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