Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron.
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We have investigated the role of iron in the intracellular biology of Legionella pneumophila in human monocytes and in the effector arm of cell-mediated immune defense against this intracellular bacterial pathogen. To determine if L. pneumophila intracellular multiplication is iron dependent, we studied the effect of the iron chelator deferoxamine on L. pneumophila infection of monocytes. Deferoxamine at 15 microM completely inhibited L. pneumophila intracellular multiplication. The inhibitory effect of deferoxamine was reversed with equimolar iron-saturated transferrin but not apotransferrin. To examine the potential role of iron in monocyte activation, we investigated the influence of iron-saturated transferrin on L. pneumophila multiplication in IFN gamma-activated monocytes. Iron transferrin, but not apotransferrin, neutralized the capacity of activated monocytes to inhibit L. pneumophila multiplication. To explore a potential mechanism by which activated monocytes might limit the availability of intracellular iron, we examined transferrin receptor expression on nonactivated and activated monocytes cultured in vitro for 5 d. By fluorescence-activated flow cytometry, activated monocytes exhibited markedly fewer transferrin receptors than nonactivated monocytes. By Scatchard analysis of 125I-transferrin binding to monocytes, nonactivated monocytes had 38,300 +/- 12,700 (mean +/- SE) transferrin binding sites, whereas activated monocytes had 10,300 +/- 1,600, a reduction of 73%. Activated and nonactivated monocytes had a similar mean Kd (1.8 +/- 0.2 nM). This study demonstrates that (a) L. pneumophila intracellular multiplication is iron dependent; (b) activated monocytes inhibit L. pneumophila multiplication by limiting the availability of intracellular iron; and (c) transferrin receptors are downregulated on IFN gamma-activated monocytes.
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IFNγ exposure lowers TFR1 levels in macrophages during intracellular infections.
“By contrast, macrophage expression of TFR1, which mediates iron delivery to endosomes, is decreased by IFNγ exposure during intracellular infections73.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [73]
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References 50 · Cited by 320
Research works printed but not linked: 3
- Dautry-Varsat, A., A. Ciechanover, and H. F. Lodish. 1983. pH and recycling of transferrin during receptor mediated endocytosis. Proc. Natl. Acad. Sci. USA. 80:2258-2262.
- Bennett, J. P. 1978. Methods in binding studies. In Neurotrans- mitter Receptor Binding. H. I. Yamamura, S. J. Enna, and M. J. Kuhar, editors. Raven Press, New York. 71-74.
- Griffith, E. 1987. Iron in biological systems. In Iron and Infec- tion: Molecular, Physiological and Clinical Aspects. J. J. Bullen and E. Griffiths, editors. John Wiley & Sons Ltd., Chichester, UK. 8-12.
- Authors
- Byrd, T. F., & Horwitz, M. A.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1989-05-01
- Volume
- 83
- Issue
- 5
- Pages
- 1457-1465
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC303847
- OpenAlex
- W2164683251
- Cited by
- 320
- References
- 50
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 10 · 2013: 17 · 2012: 7
- FWCI
- 8.89
- 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
- University of California, Los Angeles
- National Institute of Allergy and Infectious Diseases (AI22421)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Legionella and Acanthamoeba research
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Legionella pneumophila, human monocytes, interferon-gamma, iron limitation, deferoxamine, iron-saturated transferrin, apotransferrin, cell-mediated immunity, iron chelation, monocyte activation
- MeSH terms
- Adult, Cytoplasm, Humans, Interferon-gamma, Iron, Legionella, Macrophage Activation, Monocytes, Receptors, Transferrin, Transferrin, Signal Transduction
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