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Iron regulates nitric oxide synthase activity by controlling nuclear transcription.
Open accessAbstract
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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“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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 Salmonella Typhimurium infection: Heme oxygenase 1 expression affects Salmonella infection (2016) · cites this paper as Weiss et al., 1994
In the citing paper
“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]
In the citing paper
“As examples for this, iron perturbations regulate IFN-γ effector pathways by modulating ICAM-1 and HLA-DR expression on monocytes or TNFα and iNOS formation at the transcriptional level [60,141].”
From Iron in immune cell function and host defense (2021) · cites this paper as [60]
In the citing paper
“On one hand, macrophage iron overload is associated with the inhibition of IFN-γ-driven antimicrobial immune effector pathways such as nitric oxide synthase 2 (Nos2) expression, resulting in impaired control of intracellular microbes (Weiss et al., 1994; Mencacci et al., 1997; Oexle et al., 2003).”
From Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection (2017) · cites this paper as Weiss et al., 1994
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Cites
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A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity
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The L-Arginine-Nitric Oxide Pathway
Epstein, F. H., Moncada, S., & Higgs, A. (1993) · New England Journal of Medicine · doi:10.1056/nejm199312303292706 · Cited by 6,678
Nitric oxide as a secretory product of mammalian cells
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Nitric oxide: A cytotoxic activated macrophage effector molecule
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Cloning and Characterization of Inducible Nitric Oxide Synthase from Mouse Macrophages
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Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.
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Sorted by citations
Nitric oxide synthases: Roles, tolls, and controls
Nathan, C., & Xie, Q. W. (1994) · Cell · doi:10.1016/0092-8674(94)90266-6 · Cited by 2,920
THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger Gases
Maines, M. D. (1997) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.37.1.517 · Cited by 2,489
Oxidative Stress, Prooxidants, and Antioxidants: The Interplay
Rahal, A., Kumar, A., Singh, V., Yadav, B., Tiwari, R., Chakraborty, S., & Dhama, K. (2014) · BioMed Research International · doi:10.1155/2014/761264 · Cited by 1,806
Hentze, M. W., & Kühn, L. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8175 · Cited by 1,292
Self-citationMacrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989
Metadata
- 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.
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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