title: Overexpression of the dominant-negative form of interferon regulatory factor 1 in oligodendrocytes protects against experimental autoimmune encephalomyelitis.
abstract: Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS.
authors.affiliation: Rush University Medical Center, Department of Neurological Sciences, Multiple Sclerosis Center, Chicago, Illinois 60612, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ren
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Duan
authors.initials: D
authors.lastname: Tao
authors.forename: David
authors.initials: D
authors.lastname: Liebenson
authors.forename: Thomas
authors.initials: T
authors.lastname: Liggett
authors.forename: Rajendra
authors.initials: R
authors.lastname: Goswami
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Dusan
authors.initials: D
authors.lastname: Stefoski
authors.forename: Roumen
authors.initials: R
authors.lastname: Balabanov
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004586:Electrophoresis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050856:Interferon Regulatory Factor-1