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Cited by 412Iron Metabolism and DisordersNitric Oxide and Endothelin EffectsHemoglobin structure and function

Iron regulates nitric oxide synthase activity by controlling nuclear transcription.

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Weiss, G, Werner-Felmayer, G, Werner, E R, Grünewald, K, Wachter, H, Hentze, M W·1994·The Journal of experimental medicine
DOI 10.1084/jem.180.3.969PMC PMC2191642
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Abstract

Recently, it was reported that nitric oxide (NO) directly controls intracellular iron metabolism by activating iron regulatory protein (IRP), a cytoplasmic protein that regulates ferritin translation. To determine whether intracellular iron levels themselves affect NO synthase (NOS), we studied the effect of iron on cytokine-inducible NOS activity and mRNA expression in the murine macrophage cell line J774A.1. We show here that NOS activity is decreased by about 50% in homogenates obtained from cells treated with interferon gamma plus lipopolysaccharide (IFN-gamma/LPS) in the presence of 50 microM ferric iron [Fe(3+)] as compared with extracts from cells treated with IFN-gamma/LPS alone. Conversely, addition of the iron chelator desferrioxamine (100 microM) at the time of stimulation with IFN-gamma/LPS increases NOS activity up to 2.5-fold in J774 cells. These effects of changing the cellular iron state cannot be attributed to a general alteration of the IFN-gamma/LPS signal, since IFN-gamma/LPS-mediated major histocompatibility complex class II antigen expression is unaffected. Furthermore, neither was the intracellular availability of the NOS cofactor tetrahydrobiopterin altered by treatment with Fe(3+) or desferrioxamine, nor do these compounds interfere with the activity of the hemoprotein NOS in vitro. We demonstrate that the mRNA levels for NOS are profoundly increased by treatment with desferrioxamine and reduced by Fe(3+). The half-life of NOS mRNA appeared not to be significantly altered by administration of ferric ion, and NOS mRNA stability was only slightly prolonged by desferrioxamine treatment. Nuclear run-off experiments demonstrate that nuclear transcription of cytokine-inducible NOS mRNA is strongly increased by desferrioxamine whereas it is decreased by Fe(3+). Thus, this transcriptional response appears to account quantitatively for the changes in enzyme activity. Our results suggest the existence of a regulatory loop between iron metabolism and the NO/NOS pathway.

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  • Iron chelators antagonize a direct inhibitory effect of iron toward the expression of iNOS.

    “Thereby iron chelators antagonize a direct inhibitory effect of iron toward the expression of iNOS (Weiss et al., 1994; Melillo et al., 1997; Dlaska and Weiss, 1999).”

    From Iron at the interface of immunity and infection (2014) · cites this paper as Weiss et al., 1994

  • Stimulation of ferroportin expression results in iron limitation to intra-macrophage bacteria and improved control of infection, also due to stimulation of macrophage effector functions as a consequence of intracellular iron deficiency.

    “Stimulation of ferroportin expression results in iron limitation to intra-macrophage bacteria and an improved control of the infection, which is also due to stimulation of MO effector functions as a consequence of intracellular iron deficiency.”

    From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [188]

  • M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which enhances antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine IL-10.

    “In contrast, M1 macrophages enhance iron uptake and storage, and display an attenuated iron-release phenotype favoring intracellular iron sequestration and storage, which has been shown to enhance antimicrobial effector functions such as increased pro-inflammatory TNFα expression while suppressing expression of the anti-inflammatory cytokine, IL-10 (Weiss et al., 1994; Mulero et al., 2002; Fritsch”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Weiss et al., 1994

  • Reduction in intracellular iron concentrations promotes production of pro-inflammatory molecules such as TNF-α, IL-6, iNOS, or CCL-20 by activated macrophages.

    “Reduction in intracellular iron concentrations has been shown to promote the production of pro-inflammatory molecules such as TNF-α, IL-6, iNOS (nos2) or CCL-20 by activated macrophages (Weiss et al., 1994; Melillo et al., 1997; Ludwiczek et al., 2003; Oexle et al., 2003; Varesio et al., 2010), and these pathways are of importance for the control of intracellular pathogens like Salmonella (Andrews”

    From Heme oxygenase 1 controls early innate immune response of macrophages to<i>Salmonella</i>Typhimurium infection: Heme oxygenase 1 expression affects Salmonella<i>infection</i> (2016) · cites this paper as Weiss et al., 1994

  • Iron negatively affects the transcriptional expression of iNOS, thereby building a regulatory feedback loop linking cellular iron delivery to NO formation for host defense.

    “iron negatively effects the transcriptional expression of iNOS thereby building up a regulatory feedback loop linking cellular iron delivery to NO formation for host defense”

    From Iron in immune cell function and host defense (2021) · cites this paper as [60]

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Authors
Weiss, G., Werner-Felmayer, G., Werner, E. R., Grünewald, K., Wachter, H., & Hentze, M. W.
Affiliations
  • Universität Innsbruck (AT)
  • Department of Internal Medicine, University of Innsbruck, Austria.
ORCID
Venue
The Journal of experimental medicine
Publisher
Rockefeller University Press
Published
1994-09-01
Volume
180
Issue
3
Pages
969-976
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.180.3.969
PMC
PMC2191642
OpenAlex
W1976665224
Cited by
412
References
50
Citations by year
2026: 4 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 11 · 2020: 14 · 2019: 6 · 2018: 14 · 2017: 8 · 2016: 8 · 2015: 10 · 2014: 11 · 2013: 13 · 2012: 9
FWCI
12.22
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
nitric oxide synthase, iron metabolism, deferoxamine, iron(III), macrophages, interferon-gamma, lipopolysaccharide, tetrahydrobiopterin, iron regulatory proteins, MHC class II expression
MeSH terms
Amino Acid Oxidoreductases, Animals, Cell Nucleus, Cells, Cultured, Deferoxamine, Half-Life, Interferon-gamma, Iron, Macrophages, Nitric Oxide, RNA, Messenger, Transcription, Genetic, Gene Expression Regulation, Enzymologic, Nitric Oxide Synthase, Mice

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