title: Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis.
abstract: Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme required for prostaglandin E(2) (PGE(2)) biosynthesis. In this study, we examined the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We induced EAE with myelin oligodendrocyte glycoprotein(35-55) peptide in mPGES-1-deficient (mPGES-1(-/-)) and wild-type (WT) mice. First, we examined the histopathology in the early and late phases of EAE progression. Next, we measured the concentration of PGE(2) in the spinal cord and investigated the expression of mPGES-1 using immunohistochemistry. In addition, we examined the progression of the severity of EAE using an EAE score to investigate a correlation between pathological features and paralysis. In this paper, we demonstrate that WT mice showed extensive inflammation and demyelination, whereas mPGES-1(-/-) mice exhibited significantly smaller and more localized changes in the perivascular area. The mPGES-1 protein was induced in vascular endothelial cells and microglia around inflammatory foci, and PGE(2) production was increased in WT mice but not mPGES-1(-/-) mice. Furthermore, mPGES-1(-/-) mice showed a significant reduction in the maximum EAE score and improved locomotor activity. These results suggest that central PGE(2) derived from non-neuronal mPGES-1 aggravates the disruption of the vessel structure, leading to the spread of inflammation and local demyelination in the spinal cord, which corresponds to the symptoms of EAE. The inhibition of mPGES-1 may be useful for the treatment of human MS.
authors.affiliation: Medical Research Institute, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Chisen
authors.initials: C
authors.lastname: Takeuchi
authors.forename: Yoh
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Kuniko
authors.initials: K
authors.lastname: Kohyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kanato
authors.initials: K
authors.lastname: Yamagata
authors.forename: Takako
authors.initials: T
authors.lastname: Takemiya
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000503:physiopathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology; D005260:Female; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000201:enzymology*; D009103:Multiple Sclerosis / Q000503:physiopathology*; D000071876:Prostaglandin-E Synthases
chemical_list: D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse