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

Masatsugu Ohtsuki, Hiroaki Shiraishi, Taiya Kato, Risa Kuroda, Masahiro Tazawa, Chiho Sumi-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 ; Sumi-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 Sumi-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, Sumi-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; Sumi-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 - Sumi-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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