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Cytosolic phospholipase A₂–deficient mice are resistant to experimental autoimmune encephalomyelitis

¹ Department of Inflammation, Wyeth Research, Cambridge, MA 02140
² Exploratory Drug Safety, Wyeth Research, Andover, MA 01810
³ Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan

CORRESPONDENCE Suzana Marusic: smarusic{at}wyeth.com

Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A₂ (cPLA₂), 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 cPLA₂^–/– mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA₂^+/– mice, whereas the lesions in cPLA₂^–/– mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA₂^–/– mice compared with cPLA₂^+/– mice, which indicates that cPLA₂ plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA₂^–/– 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 cPLA₂ also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA₂^–/– mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA₂^–/– mice susceptible to EAE. Our data indicate that cPLA₂ plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.

Abbreviations used: 5-LO, 5-lipoxygenase; AA, arachidonic acid; AACOCF3, arachidonyl trifluoromethylketone; CNS, central nervous system; cPLA₂, cytosolic phospholipase A₂; CSF, cerebrospinal fluid; EAE, experimental autoimmune encephalomyelitis; LT, leukotriene; MCP, monocyte chemoattractant protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PAF, platelet-activating factor; PG, prostaglandin.

J.P. Leonard's present address is Genzyme Drug Discovery & Development, Waltham, MA 02451.

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