cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
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.
Ohtsuki
Masatsugu
M
Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
Shiraishi
Hiroaki
H
Kato
Taiya
T
Kuroda
Risa
R
Tazawa
Masahiro
M
Sumi-Ichinose
Chiho
C
Tada
Shin
S
Udagawa
Yasutoshi
Y
Itoh
Mitsuyasu
M
Hishida
Hitoshi
H
Ichinose
Hiroshi
H
Nagatsu
Toshiharu
T
Hagino
Yasumichi
Y
Nomura
Takahide
T
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
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