Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis

Proinflammatory cytokines, pathological iron deposition, and oxidative stre ss have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitoc hondrial uptake of [Fe-55]Cl-3-derived iron were measured in rat astroglial cultures exposed to interleukin-l beta (IL-1) or tumor necrosis factor-alp ha (TNF-alpha) alone or in combination with the heme oxygenase-l (HO-1) inh ibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta 1b (INF-P). HO-1 expression in astrocytes was evaluated by immunohistochem ical staining of spinal cord tissue derived from MS and control subjects. I L-1 beta or TNF-alpha promoted sequestration of non-transferrin-derived 55F e by astroglial mitochondria. HO-1 inhibitors, m beta itochondrial permeabi lity transition pore (MTP) blockers and antioxidants significantly attenuat ed cytokine-related mitochondrial iron sequestration in these cells. IFN-p decreased HO-1 expression and mitochondrial iron sequestration in IL-1 beta - and TNF-cr-challenged astroglia. The percentage of astrocytes coexpressin g HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was signi ficantly greater (p < 0.05) than in normal spinal cord derived from control s subjects (15.4% +/- 8.4%). HO-1 is overexpressed in MS spinal cord astrog lia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN -beta may attenuate glial HO-1 gene induction and aberrant mitochondrial ir on deposition accruing from exposure to proinflammatory cytokines.