title: The Influence of Differentially Expressed Tissue-Type Plasminogen Activator in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis.
abstract: Tissue type plasminogen activator (t-PA) has been implicated in the development of multiple sclerosis (MS) and in rodent models of experimental autoimmune encephalomyelitis (EAE). We show that levels of t-PA mRNA and activity are increased ~4 fold in the spinal cords of wild-type mice that are mice subjected to EAE. This was also accompanied with a significant increase in the levels of pro-matrix metalloproteinase 9 (pro-MMP-9) and an influx of fibrinogen. We next compared EAE severity in wild-type mice, t-PA-/- mice and T4+ transgenic mice that selectively over-express (~14-fold) mouse t-PA in neurons of the central nervous system. Our results confirm that t-PA deficient mice have an earlier onset and more severe form of EAE. T4+ mice, despite expressing higher levels of endogenous t-PA, manifested a similar rate of onset and neurological severity of EAE. Levels of proMMP-9, and extravasated fibrinogen in spinal cord extracts were increased in mice following EAE onset regardless of the absence or over-expression of t-PA wild-type. Interestingly, MMP-2 levels also increased in spinal cord extracts of T4+ mice following EAE, but not in the other genotypes. Hence, while the absence of t-PA confers a more deleterious form of EAE, neuronal over-expression of t-PA does not overtly protect against this condition with regards to symptom onset or severity of EAE.
authors.affiliation: Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Lisa Cm
authors.initials: LC
authors.lastname: Dahl
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Zeyad
authors.initials: Z
authors.lastname: Nasa
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: JieYu
authors.initials: J
authors.lastname: Chung
authors.affiliation: Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Be'eri
authors.initials: B
authors.lastname: Niego
authors.affiliation: Van Cleef Roet Centre for Nervous Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Volga
authors.initials: V
authors.lastname: Tarlac
authors.affiliation: Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Heidi
authors.initials: H
authors.lastname: Ho
authors.affiliation: Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Galle
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petratos
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Alderuccio
authors.affiliation: Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005340:Fibrinogen / Q000032:analysis / Q000378:metabolism; D017353:Gene Deletion; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D005340:Fibrinogen; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9