Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis.
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.
Mehindate
K
K
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir, Mortimer B. Davis-Jewish General Hospital, Montreal, Canada.
Sahlas
D J
DJ
Frankel
D
D
Mawal
Y
Y
Liberman
A
A
Corcos
J
J
Dion
S
S
Schipper
H M
HM
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D002712:Chlorides; D016207:Cytokines / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005290:Ferric Compounds / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007504:Iron Radioisotopes; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000201:enzymology / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002712:Chlorides; D016207:Cytokines; D005290:Ferric Compounds; D007375:Interleukin-1; D007504:Iron Radioisotopes; D012333:RNA, Messenger; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); C024555:ferric chloride