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Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide-dependent and -independent pathways following activation with gamma interferon and lipopolysaccharide.

Mulero, Victoriano, Brock, Jeremy H.·1999·Blood

DOI 10.1182/blood.v94.7.2383.419k20_2383_2389

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Abstract

To elucidate the pathways by which nitric oxide (NO) influences macrophage iron metabolism, the uptake, release, and intracellular distribution of iron in the murine macrophage cell line J774 has been investigated, together with transferrin receptor (TfR) expression and iron-regulatory protein (IRP1 and IRP2) activity. Stimulation of macrophages with interferon-γ (IFN-γ) and/or lipopolysaccharide (LPS) decreased Fe uptake from transferrin (Tf), and there was a concomitant downregulation of TfR expression. These effects were mediated by NO-dependent and NO-independent mechanisms. Addition of the NO synthase (NOS) inhibitor N-monomethyl arginine (NMMA) partially restored Fe uptake but either had no effect on or downregulated TfR expression, which suggests that NO by itself is able to affect iron availability. Analysis of the intracellular distribution of incorporated iron revealed that in IFN-γ/LPS-activated macrophages there was a decreased amount and proportion of ferritin-bound iron and a compensatory increase in insoluble iron, which probably consists mainly of iron bound to intracellular organelles. Finally, although NO released by IFN-γ/LPS-activated macrophages increased the iron-responsive element (IRE)-binding activity of both IRP1 and IRP2, IFN-γ treatment decreased IRP2 activity in an NO-independent manner. This study demonstrates that the effect of IFN-γ and/or LPS on macrophage iron metabolism is complex, and is not entirely due to either NO-or to IRP-mediated mechanisms. The overall effect is to decrease iron uptake, but not its utilization.

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Authors: Mulero, V., & Brock, J. H.
Affiliations: From the Department of Immunology and Bacteriology, Western Infirmary, University of Glasgow, Glasgow, UK; and the Department of Cell Biology, Faculty of Biology, University of Murcia, Murcia, Spain.
Western Infirmary (GB)
Venue: Blood
Publisher: American Society of Hematology
Published: 1999-10-01
Volume: 94
Issue: 7
Pages: 2383-2389
ISSN: 0006-4971 (ISSN-L)
1528-0020
DOI: 10.1182/blood.v94.7.2383.419k20_2383_2389
OpenAlex: W2144161937
Cited by: 86
References: 37
Citations by year: 2023: 1 · 2022: 1 · 2021: 5 · 2020: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 1 · 2012: 7
FWCI: 3.68
Type: journal article
Language: en
Open access: closed
Locations: Blood (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Physical Sciences › Materials Science › Metals and Alloys › Iron and Steelmaking Processes
Keywords: nitric oxide, interferon-gamma, lipopolysaccharide, transferrin receptor, iron regulatory protein 1, IRP2, iron absorption, iron-responsive element, nitric oxide synthase, J774 macrophages
MeSH terms: Animals, Cell Line, Gene Expression Regulation, Interferon-gamma, Iron, Iron-Sulfur Proteins, Kinetics, Lipopolysaccharides, Macrophages, Nitric Oxide, Receptors, Transferrin, Recombinant Proteins, Transferrin, RNA-Binding Proteins, Nitric Oxide Synthase, omega-N-Methylarginine, Iron-Regulatory Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice

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Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide-dependent and -independent pathways following activation with gamma interferon and lipopolysaccharide.

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