Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis
Abstract
Proinflammatory cytokines, pathological iron deposition, and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) alone or in combination with the heme oxygenase-1 (HO-1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta1b (INF-beta). HO-1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL-1beta or TNF-alpha promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria. HO-1 inhibitors, mitochondrial permeability transition pore (MTP) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells. IFN-beta decreased HO-1 expression and mitochondrial iron sequestration in IL-1beta- and TNF-alpha-challenged astroglia. The percentage of astrocytes coexpressing HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal spinal cord derived from controls subjects (15.4% +/- 8.4%). HO-1 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN-beta may attenuate glial HO-1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.
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Incubation with interferon β reverted cytokine-dependent induction of HO-1 and subsequent incorporation of iron into mitochondria.
“Incubation with interferon β reverted the cytokine-dependent induction of HO-1 and the subsequent incorporation of iron into mitochondria.162”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [162]
Increased HO-1 expression promoted sequestration of non-transferrin iron into the astroglial mitochondrial compartment, as assayed by 55Fe incorporation.
“Increased HO-1 expression promoted the sequestration of non-transferrin iron into the astroglial mitochondrial compartment, as assayed by 55Fe incorporation.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [162]
In-vitro studies of rat astroglial cultures showed proinflammatory cytokines (interleukin 1β and tumour necrosis factor α) increased HO-1 expression after 6 days of incubation.
“In-vitro studies of rat astroglial cultures showed that proinflammatory cytokines (ie, interleukin 1β and tumour necrosis factor α) increased HO-1 expression after 6 days of incubation.”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [162]
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- Authors
- Mehindate, K., Sahlas, D. J., Frankel, D., Mawal, Y., Liberman, A., Corcos, J., Dion, S., & Schipper, H. M.
- Affiliations
- Jewish General Hospital (CA)
- McGill University (CA)
- Corresponding author
- Schipper, H. M.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2001-06
- Volume
- 77
- Issue
- 5
- Pages
- 1386-1395
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1902487112
- Cited by
- 129
- References
- 54
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 5 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 5 · 2014: 7 · 2013: 3 · 2012: 3
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fonds de Recherche du Québec - Santé
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- heme oxygenase-1, multiple sclerosis, inflammatory cytokines, IL-1β, TNF-α, astrocytes, iron sequestration, interferon-beta, experimental autoimmune encephalomyelitis, oxidative stress, mitochondrial permeability transition pore, tin mesoporphyrin, dexamethasone
- MeSH terms
- Animals, Cells, Cultured, Chlorides, Encephalomyelitis, Autoimmune, Experimental, Female, Ferric Compounds, Heme Oxygenase (Decyclizing), Humans, Immunohistochemistry, Interleukin-1, Iron, Iron Radioisotopes, Mitochondria, Multiple Sclerosis, Neuroglia, RNA, Messenger, Spinal Cord, Subcellular Fractions, Transferrin, Tumor Necrosis Factor-alpha, Blotting, Northern, Cytokines, Rats, Sprague-Dawley, Rats
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