title: Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis.
abstract: The phospholipase A(2) (PLA(2)) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA(2)s (cPLA(2) GIVA and iPLA(2) GVIA) and two of the secreted PLA(2)s (sPLA(2) GIIA and sPLA(2) GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA(2) GIVA plays a role in the onset, and iPLA(2) GVIA in the onset and progression of EAE. We also show a potential role for sPLA(2) in the later remission phase. These studies demonstrate that selective inhibition of iPLA(2) can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA(2) is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA(2) might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis.
authors.affiliation: Center for Research in Neuroscience, McGill University Health Center Research Institute, Livingston Hall, Room L7-210, 1650 Cedar Ave., Montreal, Quebec, Canada H3G 1A4.
authors.forename: Athena
authors.initials: A
authors.lastname: Kalyvas
authors.forename: Constantinos
authors.initials: C
authors.lastname: Baskakis
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
authors.forename: Daren
authors.initials: D
authors.lastname: Stephens
authors.forename: Rubèn
authors.initials: R
authors.lastname: López-Vales
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Lu
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.forename: Samuel
authors.initials: S
authors.lastname: David
mesh_terms: D000328:Adult; D000577:Amides / Q000627:therapeutic use; D000818:Animals; D016207:Cytokines / Q000276:immunology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005227:Fatty Acids / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005466:Fluorocarbons; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007659:Ketones / Q000627:therapeutic use; D008264:Macrophages / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000201:enzymology / Q000235:genetics; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000737:chemistry / Q000502:physiology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013116:Spinal Cord / Q000201:enzymology*; D013601:T-Lymphocytes / Q000201:enzymology; D055815:Young Adult
chemical_list: C533806:1,1,1,2,2-pentafluoro-7-phenylheptan-3-one; C541509:AX 059; C541510:AX 115; D000577:Amides; D016207:Cytokines; D004791:Enzyme Inhibitors; C541511:FKGK2 compound; D005227:Fatty Acids; D005466:Fluorocarbons; D007659:Ketones; D064801:Phospholipase A2 Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D054467:Phospholipases A2