title: Differential upregulation of heme oxygenase-1 (HSP32) in glial cells after oxidative stress and in demyelinating disorders.
abstract: Oxidative stress is implicated in the pathogenesis of demyelinating disorders and inflammatory responses. Heme oxygenase-1 (HO-1; HSP32) is a small heat shock protein (HSP) with enzymatic activity, which is inducible by oxidative stress. In this study we analyzed autopsy and biopsy brain samples of patients with multiple sclerosis (MS) and ADEM (acute disseminated leucoencephalomyelits) and spinal cord lesions of mouse EAE (experimental autoimmune encephalomyelitis), which was actively induced by immunization with myelin oligodendrocyte glycoprotein (MOG35-55) peptide, for the presence of HO-1. HO-1 was observed in glial cells during different stages: (1) during acute phases of mainly inflammatory diseases (EAE and ADEM) expression of HO-1 was prominent in microglia/macrophages and astrocytes, and upregulation correlated with inflammation, and (2) in early MS lesions HO-1 was expressed in oligodendrocytes. Furthermore, in glial cell cultures, we can show that upregulation of HO-1 in oligodendrocytes was paralleled by severe morphological damage. Oligodendrocytes underwent apoptotic cell death at a concentration of hydrogen peroxide (50-200 microM) which did not affect astrocytes or microglia. Using oligodendroglial OLN-93 cells, we demonstrate that oxidative stress led to mitochondrial impairment and the disorganization of the microtubule network. Zinc protoporphyrin, an inhibitor of HO-1, augmented the cytotoxic consequences of hydrogen peroxide in OLN-93 cells. Hence, the presence of HO-1 in EAE, ADEM, and MS points to the involvement of oxidative stress and a role of HO-1 in the pathogenesis of the diseases. The data suggest that stress-induced HO-1 initially plays a protective role, while its chronic upregulation, might contribute to oligodendroglial cell death rather than providing protection.
authors.affiliation: Department of Biology, Molecular Neurobiology, University of Oldenburg, D-26111 Oldenburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stahnke
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.forename: Anne
authors.initials: A
authors.lastname: Netzler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Landsberg
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1