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Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.
Open accessAbstract
We have investigated the regulation of key human iron binding proteins in mononuclear phagocytes by IFN gamma and iron transferrin. In a previous study, we demonstrated that IFN gamma downregulates the expression on human monocytes of transferrin receptors, the major source of iron for the cell. In the present study, we show that IFN gamma also downregulates the intracellular concentration of ferritin, the major iron storage protein in the cell. By radioimmunoassay, the mean ferritin content of nonactivated monocytes was 361 +/- 107 fg/monocyte (mean +/- SEM) whereas the mean ferritin content of IFN gamma-activated monocytes was 64 +/- 13 fg/monocyte, an 82% reduction with activation (P < 0.01, t test). Consistent with its downregulating effect on these iron proteins, IFN gamma treatment also results in decreased iron incorporation. IFN gamma-activated monocytes incorporated 33% less iron from 59Fe-transferrin than nonactivated monocytes (P < 0.05, t test). Gel filtration chromatography revealed that incorporated iron is located primarily in ferritin in both nonactivated and IFN gamma-activated monocytes. Ferritin in IFN gamma-activated monocytes is saturated with approximately three times as much 59Fe as ferritin in nonactivated monocytes. We have also explored the effect of iron transferrin on transferrin receptor expression and intracellular ferritin content in human monocytes. We have found that iron transferrin markedly upregulates both transferrin receptor expression and intracellular ferritin content in both nonactivated (2.3- and 1.3-fold, respectively) and IFN gamma-activated (3.4- and 2.9-fold, respectively) monocytes. This study demonstrates that transferrin receptor expression and intracellular ferritin content in human monocytes is unidirectionally and coordinately upregulated by iron transferrin and unidirectionally and coordinately downregulated by IFN gamma.
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“During infections, pro-inflammatory cytokines play an essential role in hepcidin-independent sequestration of iron. Tumour necrosis factor alpha (TNF-α), interleukins (IL-1 and IL-6), and interferon gamma (IFN-γ) increase uptake of free iron by macrophages and transferrin through upregulation of transferrin receptor proteins (Byrd and Horwitz, 1993; Ludwiczek et al., 2003; Drakesmith and Prentice,”
From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as Byrd and Horwitz, 1993
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“Second, TNF-α, IL-1, IL-6, and interferon-gamma (IFN-γ) affect macrophage iron homeostasis by different avenues. They increase the uptake of transferrin and non-transferrin bound iron by modulating the expression of transferrin receptor-1 and divalent metal transporter-1, respectively (Byrd and Horwitz, 1993; Fahmy and Young, 1993; Mulero and Brock, 1999; Ludwiczek et al., 2003).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Byrd and Horwitz, 1993
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“In addition, many of these cytokines as well as the anti-inflammatory cytokines IL-4, IL-10, and IL-13 promote efficient iron storage within macrophages/monocytes by increasing the expression of ferritin, both at the transcriptional and posttranscriptional level (Byrd and Horwitz, 1993; Weiss et al., 1997a; Mulero and Brock, 1999; Arosio and Levi, 2002; Tilg et al., 2002; Ludwiczek et al., 2003).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Byrd and Horwitz, 1993
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“The latter may be also referred to a direct inhibitory effect of IFN-γ on TfR expression in monocytes, thereby decreasing iron concentration in the mycobacteria containing phagosome (174, 181) (Fig. 2).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [181]
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“First, cytokines such as IFN-γ inhibit the transcriptional expression of transferrin receptor (TfR).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [181]
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Citations
Cites
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Oxidation-Reduction and the Molecular Mechanism of a Regulatory RNA-Protein Interaction
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Research works printed but not linked: 1
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Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989
Schaible, U. E., & Kaufmann, S. H. E. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro1046 · Cited by 945
Iron Homeostasis and the Inflammatory Response
Wessling-Resnick, M. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104804 · Cited by 480
Mechanisms of Therapeutic Activity for Gallium
Bernstein, L. R. (1998) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01383-8 · Cited by 458
Legionella PneumophilaPathogenesis: A Fateful Journey from Amoebae to Macrophages
Swanson, M. S., & Hammer, B. K. (2000) · Annual Review of Microbiology · doi:10.1146/annurev.micro.54.1.567 · Cited by 402
Metadata
- Authors
- Byrd, T. F., & Horwitz, M. A.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-03-01
- Volume
- 91
- Issue
- 3
- Pages
- 969-976
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC288049
- OpenAlex
- W1969289450
- Cited by
- 149
- References
- 43
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 8 · 2013: 3 · 2012: 7
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- American Cancer Society
- National Institutes of Health (5r01ai028825-05, 5r01ai022421-08, CA16042)
- National Cancer Institute (CA-16 042, P30CA016042)
- National Institute of Allergy and Infectious Diseases (AI22421, AI-28825)
- Jonsson Comprehensive Cancer Center
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- transferrin receptor, ferritin, monocytes, mononuclear phagocytes, interferon-gamma, iron absorption, iron metabolism, iron storage, receptor regulation
- MeSH terms
- Adult, Cells, Cultured, Ferritins, Humans, Interferon-gamma, Iron, Kinetics, Lymphocytes, Monocytes, Receptors, Transferrin, Recombinant Proteins, Transferrin, Down-Regulation, Up-Regulation
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