Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis.
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.
Marusic
Suzana
S
Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA. smarusic@wyeth.com
Leach
Michael W
MW
Pelker
Jeffrey W
JW
Azoitei
Mihai L
ML
Uozumi
Naonori
N
Cui
Junqing
J
Shen
Marina W H
MW
DeClercq
Charlene M
CM
Miyashiro
Joy S
JS
Carito
Brenda A
BA
Thakker
Paresh
P
Simmons
David L
DL
Leonard
John P
JP
Shimizu
Takao
T
Clark
James D
JD
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*
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