Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons
Open accessAbstract
Both inflammatory processes associated with microglia activation and abnormal iron deposit in dopaminergic neurons are involved in the pathogenesis of Parkinson's disease (PD). However, the relationship between neuroinflammation and iron accumulation was not fully elucidated. In the present study, we aimed to investigate whether the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) released by microglia, could affect cellular iron transportation in primary cultured ventral mesencephalic (VM) neurons. The results showed that IL-1β or TNF-α treatment led to increased ferrous iron influx and decreased iron efflux in these cells, due to the upregulation of divalent metal transporter 1 with the iron response element (DMT1+IRE) and downregulation of ferroportin1 (FPN1). Increased levels of iron regulatory protein 1 (IRP1), transferrin receptor 1 (TfR1) and hepcidin were also observed in IL-1β or TNF-α treated VM neurons. IRP1 upregulation could be fully abolished by co-administration of radical scavenger N-acetyl-l-cysteine and inducible NO synthetase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride. Further experiments demonstrated that IL-1β and TNF-α release was remarkably enhanced by iron load in activated microglia triggered by lipopolysaccharide or 1-methyl-4-phenylpyridinium (MPP(+)). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice, salicylate application could not block DMT1+IRE upregulation in dopaminergic neurons of substantia nigra. These results suggested that IL-1β and TNF-α released by microglia, especially under the condition of iron load, might contribute to iron accumulation in VM neurons by upregulating IRP1 and hepcidin levels through reactive oxygen/nitrogen species production. This might provide a new insight into unraveling that microglia might aggravate this iron mediated neuropathologies in PD.
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Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores through modulation of iron regulatory proteins including hepcidin, FPN, ferritin, and DMT1.
“Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores by modulating the expression and activity of various iron regulatory proteins including hepcidin, FPN, ferritin, and the iron importer divalent metal transporter 1 (DMT1) [25–30].”
From The utility of iron chelators in the management of inflammatory disorders (2015) · cites this paper as [27]
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References 55 · Cited by 150
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- Authors
- Wang, J., Song, N., Jiang, H., Wang, J., & Xie, J.
- Affiliations
- Qingdao University (CN)
- Corresponding author
- Xie, Junxia
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 1832
- Issue
- 5
- Pages
- 618-625
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2023931520
- Cited by
- 150
- References
- 55
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 17 · 2023: 15 · 2022: 14 · 2021: 17 · 2020: 8 · 2019: 14 · 2018: 9 · 2017: 1 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 3
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of China (2011CB504102)
- National Natural Science Foundation of China (30930036, 31171031, 30900477)
- Department of Science and Technology of Shandong Province (ZR2012HZ005, BS2010SW005)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Parkinson's disease, iron accumulation, neuroinflammation, microglial activation, inflammatory cytokines, IL-1β, TNF-α, iron regulatory protein 1, ferroportin 1, DMT1, iron transport, reactive oxygen species, reactive nitrogen species, nitric oxide, hepcidin, dopaminergic neurons, substantia nigra, MPTP, salicylates, lipopolysaccharide
- MeSH terms
- Solute Carrier Family 11, Member 2, Animals, Animals, Newborn, Anti-Inflammatory Agents, Non-Steroidal, Biological Transport, Cells, Cultured, Iron, Male, Mesencephalon, Mice, Inbred C57BL, Neurons, Salicylates, Tumor Necrosis Factor-alpha, Tyrosine 3-Monooxygenase, Blotting, Western, Rats, Sprague-Dawley, Reactive Oxygen Species, Microglia, MPTP Poisoning, Antimicrobial Cationic Peptides, Reactive Nitrogen Species, Cation Transport Proteins, Iron Regulatory Protein 1, Mice, Rats, Interleukin-1beta, Hepcidins
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