Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization

Joon Hong Park, Hee Jun Na, Young-Guen Kwon, Kwon Soo Ha, Seon Jin Lee, Chun Ki Kim, Kwang Soon Lee, Toshie Yoneyama, Kazuyuki Hatakeyama, Peter K.M. Kim, Timothy R. Billiar, Young Myeong Kim

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Nitric oxide (NO) regulates the biological activity of many enzymes and other functional proteins as well as gene expression. In this study, we tested whether pretreatment with NO regulates NO production in response to cytokines in cultured rat hepatocytes. Hepatocytes were recovered in fresh medium for 24 h following pretreatment with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and stimulated to express the inducible NO synthase (iNOS) with interleukin-1β and interferon-γ or transfected with the human iNOS gene. NO pretreatment resulted in a significant increase in NO production without changing iNOS expression for both conditions. This effect, which did not occur in macrophages and smooth muscle cells, was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO2-, or NO3- did not increase the cytokine-induced NO production. SNAP pretreatment increased cytosolic iNOS activity measured only in the absence of exogenous tetrahydrobiopterin (BH4). SNAP pretreatment suppressed the level of GTP cyclohydrolase I (GTPCHI) feedback regulatory protein (GFRP) and increased GTPCHI activity without changing GTPCHI protein level. SNAP pretreatment also increased total cellular levels of biopterin and active iNOS dimer. These results suggest that SNAP pretreatment increased NO production from iNOS by elevating cellular BH4 levels and promoting iNOS subunit dimerization through the suppression of GFRP levels and subsequent activation of GTPCHI.

Original languageEnglish
Pages (from-to)47073-47079
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number49
DOIs
Publication statusPublished - 2002 Dec 6

Fingerprint

GTP Cyclohydrolase
Dimerization
Nitric Oxide Synthase Type II
Penicillamine
Rats
Hepatocytes
Nitric Oxide
Nitric Oxide Synthase
Cytokines
Feedback
Proteins
Biopterin
Cells
Nitric Oxide Donors
Macrophages
Bioactivity
Interleukin-1
Gene expression
Dimers
Interferons

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Park, Joon Hong ; Na, Hee Jun ; Kwon, Young-Guen ; Ha, Kwon Soo ; Lee, Seon Jin ; Kim, Chun Ki ; Lee, Kwang Soon ; Yoneyama, Toshie ; Hatakeyama, Kazuyuki ; Kim, Peter K.M. ; Billiar, Timothy R. ; Kim, Young Myeong. / Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 49. pp. 47073-47079.
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abstract = "Nitric oxide (NO) regulates the biological activity of many enzymes and other functional proteins as well as gene expression. In this study, we tested whether pretreatment with NO regulates NO production in response to cytokines in cultured rat hepatocytes. Hepatocytes were recovered in fresh medium for 24 h following pretreatment with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and stimulated to express the inducible NO synthase (iNOS) with interleukin-1β and interferon-γ or transfected with the human iNOS gene. NO pretreatment resulted in a significant increase in NO production without changing iNOS expression for both conditions. This effect, which did not occur in macrophages and smooth muscle cells, was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO2-, or NO3- did not increase the cytokine-induced NO production. SNAP pretreatment increased cytosolic iNOS activity measured only in the absence of exogenous tetrahydrobiopterin (BH4). SNAP pretreatment suppressed the level of GTP cyclohydrolase I (GTPCHI) feedback regulatory protein (GFRP) and increased GTPCHI activity without changing GTPCHI protein level. SNAP pretreatment also increased total cellular levels of biopterin and active iNOS dimer. These results suggest that SNAP pretreatment increased NO production from iNOS by elevating cellular BH4 levels and promoting iNOS subunit dimerization through the suppression of GFRP levels and subsequent activation of GTPCHI.",
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Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization. / Park, Joon Hong; Na, Hee Jun; Kwon, Young-Guen; Ha, Kwon Soo; Lee, Seon Jin; Kim, Chun Ki; Lee, Kwang Soon; Yoneyama, Toshie; Hatakeyama, Kazuyuki; Kim, Peter K.M.; Billiar, Timothy R.; Kim, Young Myeong.

In: Journal of Biological Chemistry, Vol. 277, No. 49, 06.12.2002, p. 47073-47079.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nitric oxide (NO) pretreatment increases cytokine-induced NO production in cultured rat hepatocytes by suppressing GTP cyclohydrolase I feedback inhibitory protein level and promoting inducible NO synthase dimerization

AU - Park, Joon Hong

AU - Na, Hee Jun

AU - Kwon, Young-Guen

AU - Ha, Kwon Soo

AU - Lee, Seon Jin

AU - Kim, Chun Ki

AU - Lee, Kwang Soon

AU - Yoneyama, Toshie

AU - Hatakeyama, Kazuyuki

AU - Kim, Peter K.M.

AU - Billiar, Timothy R.

AU - Kim, Young Myeong

PY - 2002/12/6

Y1 - 2002/12/6

N2 - Nitric oxide (NO) regulates the biological activity of many enzymes and other functional proteins as well as gene expression. In this study, we tested whether pretreatment with NO regulates NO production in response to cytokines in cultured rat hepatocytes. Hepatocytes were recovered in fresh medium for 24 h following pretreatment with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and stimulated to express the inducible NO synthase (iNOS) with interleukin-1β and interferon-γ or transfected with the human iNOS gene. NO pretreatment resulted in a significant increase in NO production without changing iNOS expression for both conditions. This effect, which did not occur in macrophages and smooth muscle cells, was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO2-, or NO3- did not increase the cytokine-induced NO production. SNAP pretreatment increased cytosolic iNOS activity measured only in the absence of exogenous tetrahydrobiopterin (BH4). SNAP pretreatment suppressed the level of GTP cyclohydrolase I (GTPCHI) feedback regulatory protein (GFRP) and increased GTPCHI activity without changing GTPCHI protein level. SNAP pretreatment also increased total cellular levels of biopterin and active iNOS dimer. These results suggest that SNAP pretreatment increased NO production from iNOS by elevating cellular BH4 levels and promoting iNOS subunit dimerization through the suppression of GFRP levels and subsequent activation of GTPCHI.

AB - Nitric oxide (NO) regulates the biological activity of many enzymes and other functional proteins as well as gene expression. In this study, we tested whether pretreatment with NO regulates NO production in response to cytokines in cultured rat hepatocytes. Hepatocytes were recovered in fresh medium for 24 h following pretreatment with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and stimulated to express the inducible NO synthase (iNOS) with interleukin-1β and interferon-γ or transfected with the human iNOS gene. NO pretreatment resulted in a significant increase in NO production without changing iNOS expression for both conditions. This effect, which did not occur in macrophages and smooth muscle cells, was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO2-, or NO3- did not increase the cytokine-induced NO production. SNAP pretreatment increased cytosolic iNOS activity measured only in the absence of exogenous tetrahydrobiopterin (BH4). SNAP pretreatment suppressed the level of GTP cyclohydrolase I (GTPCHI) feedback regulatory protein (GFRP) and increased GTPCHI activity without changing GTPCHI protein level. SNAP pretreatment also increased total cellular levels of biopterin and active iNOS dimer. These results suggest that SNAP pretreatment increased NO production from iNOS by elevating cellular BH4 levels and promoting iNOS subunit dimerization through the suppression of GFRP levels and subsequent activation of GTPCHI.

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