title: Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A2alpha (cPLA2alpha), which initiates production of prostaglandins, leukotrienes, and platelet-activating factor, is present in EAE lesions. Using myelin oligodendrocyte glycoprotein (MOG) immunization, as well as an adoptive transfer model, we showed that cPLA2alpha-/- mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA2alpha+/- mice, whereas the lesions in cPLA2alpha-/- mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA2alpha-/- mice compared with cPLA2alpha+/- mice, which indicates that cPLA2alpha plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA2alpha-/- mice, transferred into WT mice, induced EAE with delayed onset and lower severity compared with EAE that was induced by control cells; this indicates that cPLA2alpha also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA2alpha-/- mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA2alpha-/- mice susceptible to EAE. Our data indicate that cPLA2alpha plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.
authors.affiliation: Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA. smarusic@wyeth.com
authors.forename: Suzana
authors.initials: S
authors.lastname: Marusic
authors.forename: Michael W
authors.initials: MW
authors.lastname: Leach
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pelker
authors.forename: Mihai L
authors.initials: ML
authors.lastname: Azoitei
authors.forename: Naonori
authors.initials: N
authors.lastname: Uozumi
authors.forename: Junqing
authors.initials: J
authors.lastname: Cui
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Charlene M
authors.initials: CM
authors.lastname: DeClercq
authors.forename: Joy S
authors.initials: JS
authors.lastname: Miyashiro
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Carito
authors.forename: Paresh
authors.initials: P
authors.lastname: Thakker
authors.forename: David L
authors.initials: DL
authors.lastname: Simmons
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D003600:Cytosol / Q000201:enzymology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D005260:Female; D054513:Group IV Phospholipases A2; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010741:Phospholipases A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D018664:Interleukin-12; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2