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Published 19 September 2005. doi:10.1084/jem.20050665
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 6, 841-851
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ARTICLE

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

Suzana Marusic1, Michael W. Leach2, Jeffrey W. Pelker1, Mihai L. Azoitei1, Naonori Uozumi3, Junqing Cui1, Marina W.H. Shen1, Charlene M. DeClercq1, Joy S. Miyashiro1, Brenda A. Carito2, Paresh Thakker1, David L. Simmons1, John P. Leonard1, Takao Shimizu3, and James D. Clark1

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{alpha} (cPLA2{alpha}), 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{alpha}–/– mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA2{alpha}+/– mice, whereas the lesions in cPLA2{alpha}–/– mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA2{alpha}–/– mice compared with cPLA2{alpha}+/– mice, which indicates that cPLA2{alpha} plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA2{alpha}–/– 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{alpha} also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA2{alpha}–/– mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA2{alpha}–/– mice susceptible to EAE. Our data indicate that cPLA2{alpha} 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{alpha}, cytosolic phospholipase A2{alpha}; 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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