Abstract
Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to PGs via the cyclooxygenase 1 and 2 pathways and to leukotrienes via the 5-lipoxygenase pathway. We used adoptive transfer and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in two different strains of mice (SJL or C57BL/6) to demonstrate that blockade of cPLA(2)α with a highly specific small-molecule inhibitor during the tissue-damage effector phase abrogates the clinical manifestation of disease. Using the adoptive transfer model in SJL mice, we demonstrated that the blockade of cPLA(2)α during the effector phase of disease was more efficacious in ameliorating the disease pathogenesis than the blockade of each of the downstream enzymes, cyclooxygenase-1/2 and 5-lipooxygenase. Similarly, blockade of cPLA(2)α was highly efficacious in ameliorating disease pathogenesis during the effector phase of EAE in the adoptive transfer model of EAE in C57BL/6 mice. Investigation of the mechanism of action indicates that cPLA(2)α inhibitors act on APCs to diminish their ability to induce Ag-specific effector T cell proliferation and proinflammatory cytokine production. Furthermore, cPLA(2)α inhibitors may prevent activation of CNS-resident microglia and may increase oligodendrocyte survival. Finally, in a relapsing-remitting model of EAE in SJL mice, therapeutic administration of a cPLA(2)α inhibitor, starting from the peak of disease or during remission, completely protected the mice from subsequent relapses.
MeSH terms
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Adoptive Transfer
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Animals
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Antigen-Presenting Cells / enzymology
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / pathology
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Arachidonate 5-Lipoxygenase / genetics
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Arachidonate 5-Lipoxygenase / immunology
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Arachidonate 5-Lipoxygenase / metabolism
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / immunology
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Cyclooxygenase 1 / genetics
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Cyclooxygenase 1 / immunology
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Cyclooxygenase 1 / metabolism
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Cyclooxygenase 2
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Cytokines / genetics
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Cytokines / immunology
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Cytokines / metabolism
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Encephalomyelitis, Autoimmune, Experimental / enzymology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control*
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Enzyme Inhibitors / pharmacology*
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Female
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Group IV Phospholipases A2 / antagonists & inhibitors*
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Group IV Phospholipases A2 / genetics
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Group IV Phospholipases A2 / immunology
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Group IV Phospholipases A2 / metabolism
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Humans
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Microglia / enzymology
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Microglia / immunology
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Microglia / pathology
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Multiple Sclerosis / enzymology
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Multiple Sclerosis / genetics
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Multiple Sclerosis / immunology
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Multiple Sclerosis / pathology
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Multiple Sclerosis / prevention & control*
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Oligodendroglia / enzymology
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Oligodendroglia / immunology
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Oligodendroglia / pathology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
Substances
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Cytokines
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Enzyme Inhibitors
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Inflammation Mediators
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Membrane Proteins
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Arachidonate 5-Lipoxygenase
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Ptgs2 protein, mouse
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Cyclooxygenase 1
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Cyclooxygenase 2
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Ptgs1 protein, mouse
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Group IV Phospholipases A2