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Cited by 149Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.

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Byrd, T F, Horwitz, M A·1993·Journal of Clinical Investigation
DOI 10.1172/jci116318PMC PMC288049
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Abstract

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 TNF-α, IL-1, IL-6, and IFN-γ increase uptake of free iron by macrophages and transferrin through upregulation of transferrin receptor proteins.

    “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

    The Discussion says IFN-γ downregulates transferrin receptor expression in human mononuclear phagocytes—the opposite of the claimed upregulation. It attributes receptor upregulation to iron-saturated transferrin, while discussing increased iron storage with IL-1 and TNF-α; the cited passages do not establish the claimed mechanism for all four cytokines. (LLM, conf=0.90)

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  • TNF-α, IL-1, IL-6, and IFN-γ affect macrophage iron homeostasis by increasing the uptake of transferrin and non-transferrin bound iron via modulating the expression of transferrin receptor-1 and divalent metal transporter-1.

    “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

    The Results and Discussion report the opposite of the claimed increase for IFN-γ: activated monocytes downregulate transferrin receptors and incorporate less transferrin-bound iron, with a reported 33% reduction in uptake. The paper discusses IL-1 and TNF-α in relation to iron storage, but does not establish the claimed increase in uptake through divalent metal transporter-1 or an effect of IL-6. (LLM, conf=0.90)

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  • Many cytokines as well as anti-inflammatory cytokines IL-4, IL-10, and IL-13 promote efficient iron storage within macrophages/monocytes by increasing ferritin expression at transcriptional and posttranscriptional levels.

    “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

    The Discussion reports that IL-1 and TNF-α stimulate mononuclear phagocytes to synthesize ferritin and store more intracellular iron. It does not support the claim about IL-4, IL-10, or IL-13, or establish that these cytokines increase ferritin through both transcriptional and posttranscriptional mechanisms. The paper instead reports that IFN-γ lowers ferritin content in activated monocytes (Introduction; results passage [5]). (LLM, conf=0.88)

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  • IFN-γ directly inhibits TfR expression in monocytes, thereby decreasing iron concentration in the mycobacteria-containing phagosome.

    “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]

  • Cytokines such as IFN-γ inhibit the transcriptional expression of transferrin receptor (TfR).

    “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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Research works printed but not linked: 1

  1. Methods in Enzymology: Peptide Growth Factors. Part B. 1987. Edited by D. Barnes, D., and D. A. Sirbasku, editors. Academic Press Inc. Harcourt Brace Jovanovich, New York. p. 274.

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Authors
Byrd, T. F., & Horwitz, M. A.
Affiliations
University of California, Los Angeles (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1993-03-01
Volume
91
Issue
3
Pages
969-976
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci116318
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
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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