Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13
Abstract
Macrophage effector functions are influenced by their iron status and by shifts in the balance between type 1 Th1 and Th2 cells. To elucidate the influence of the Th2 cytokines IL-4 and IL-13 on macrophage iron metabolism, we investigated activated primary mouse macrophages and the murine macrophage cell line J774. Stimulation of J774 cells and primary macrophages with IFN-gamma/LPS activates the RNA binding affinities of iron regulatory protein-1 (IRP-1) and IRP-2 for iron-responsive elements, leading to translational repression of the iron storage protein ferritin. Activation of IRP-1 and IRP-2 is caused by increased formation of nitric oxide (NO) via stimulation of the inducible NO synthase by IFN-gamma/LPS. Treatment of macrophages with IL-4 and/or IL-13 before stimulation with IFN-gamma/LPS suppresses NO formation and IRP activation, with concomitantly enhanced ferritin synthesis despite a small reduction in ferritin heavy chain mRNA levels. The mRNA levels for the membrane receptor for iron uptake, transferrin receptor (TfR), decrease following stimulation with IFN-gamma/LPS, although IRP-mediated stabilization of the TfR mRNA would have been expected. This as yet unidentified proximal inhibitory signal by IFN-gamma/LPS is antagonized by IL-4 and/or IL-13, which leads to increased TfR mRNA expression in an IRP-independent manner. Thus, IL-4 and IL-13 regulate the iron metabolism of activated macrophages by at least two different pathways: first, by opposing NO-mediated IRP activation, thereby increasing ferritin translation; and second, by an IRP-independent augmentation of TfR mRNA expression. We suggest that IL-4 and IL-13 may enhance iron uptake and storage in activated macrophages and thereby contribute to down-regulation of macrophage effector functions.
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IL-4 and IL-13 enhance TFR1 mRNA expression and FT translation to foster iron sequestration in the myeloid compartment.
“the antiinflammatory cytokines IL-4 and IL-13 enhance TFR1 mRNA expression and FT translation to foster iron sequestration in the myeloid compartment (Weiss et al., 1997).”
From Iron in infection and immunity (2020) · cites this paper as Weiss et al., 1997
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 Weiss et al., 1997a
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Self-citation
- Authors
- Weiss, G., Bogdan, C., & Hentze, M. W.
- Affiliations
- European Molecular Biology Laboratory (DE)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-01-01
- Volume
- 158
- Issue
- 1
- Pages
- 420-425
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2131168537
- Cited by
- 177
- References
- 0
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 2 · 2014: 6 · 2013: 4 · 2012: 5
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- IL-4, IL-13, iron regulatory proteins, ferritin, transferrin receptor, nitric oxide, inducible nitric oxide synthase, Th2 cytokines, iron-responsive element, macrophage effector function, iron absorption
- MeSH terms
- Animals, Base Sequence, Cell Line, Iron, Iron-Sulfur Proteins, Macrophages, Molecular Sequence Data, Nitric Oxide, Receptors, Transferrin, Interleukin-4, RNA-Binding Proteins, Interleukin-13, Iron-Regulatory Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice
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