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Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses.

Author(s): Marusic S, Thakker P, Pelker JW, Stedman NL, Lee KL, McKew JC, Han L, Xu X, Wolf SF, Borey AJ, Cui J, Shen MW, Donahue F, Hassan-Zahraee M, Leach MW, Shimizu T, Clark JD

Affiliation(s): Hooke Laboratories Inc., Lawrence, MA 01843, United States. marusic@hookelabs.com

Publication date & source: 2008-11-15, J Neuroimmunol., 204(1-2):29-37.

Publication type: Research Support, Non-U.S. Gov't

Cytosolic phospholipase A2 alpha (cPLA2 alpha) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to prostaglandins via the cyclooxygenase (COX) 1/2 pathways, and leukotrienes via the 5-lipoxygenase (LO) pathway. We utilized inhibitors of cPLA2 alpha, COX-1/2 and 5-LO to determine the potential roles of these enzymes in development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Blocking cPLA2 alpha prevented EAE development and greatly reduced antigen-induced production of Th1-type cytokines and IL-17. Blocking COX-1/2 delayed onset and reduced severity of EAE, and reduced production of Th1-type cytokines, but not IL-17. Blocking 5-LO delayed onset and reduced cumulative severity of EAE, but did not reduce production of Th1-type cytokines or IL-17. Finally, blockade of cPLA2 alpha from the onset of clinical EAE reduced duration of EAE relapses. Therefore, cPLA2 alpha represents a potential therapeutic target for treatment of MS.

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