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Proinflammatory cytokines promote glial heme oxygenase‐1 expression and mitochondrial iron deposition: implications for multiple sclerosis
Author(s) -
Mehindate K.,
Sahlas D. J.,
Frankel D.,
Mawal Y.,
Liberman A.,
Corcos J.,
Dion S.,
Schipper H. M.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00354.x
Subject(s) - proinflammatory cytokine , heme oxygenase , experimental autoimmune encephalomyelitis , tumor necrosis factor alpha , chemistry , biology , immunology , inflammation , heme , biochemistry , enzyme
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‐1β (IL‐1β) or tumor necrosis factor‐α (TNF‐α) alone or in combination with the heme oxygenase‐1 (HO‐1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon β1b (INF‐β). HO‐1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL‐1β or TNF‐α 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‐β decreased HO‐1 expression and mitochondrial iron sequestration in IL‐1β‐ and TNF‐α‐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‐β may attenuate glial HO‐1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.