Proinflammatory cytokines promote glial heme oxygenase‐1 expression and mitochondrial iron deposition: implications for multiple sclerosis
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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 [55Fe]Cl3‐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 55Fe 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.
