Abstract
Decreased IL-2 production in systemic lupus erythematosus (SLE) represents a central component of the disease immunopathology. We report that the message, protein, and enzymatic activity of the catalytic subunit of protein phosphatase 2A (PP2Ac), but not PP1, are increased in patients with SLE regardless of disease activity and treatment and in a disease-specific manner. Treatment of SLE T cells with PP2Ac-siRNA decreased the protein levels and activity of PP2Ac in a specific manner and increased the levels of phosphorylated cAMP response element-binding protein and its binding to the IL2 and c-fos promoters, as well as increased activator protein 1 activity, causing normalization of IL-2 production. Our data document increased activity of PP2A as a novel SLE disease-specific abnormality and define a distinct mechanism whereby it represses IL-2 production. We propose the use of PP2Ac-siRNA as a novel tool to correct T cell IL-2 production in SLE patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Catalytic Domain
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / biosynthesis
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Cyclic AMP Response Element-Binding Protein / genetics
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Down-Regulation / physiology*
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Female
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Humans
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Immunoglobulin G / blood
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Immunoglobulin G / physiology
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Interleukin-2 / antagonists & inhibitors*
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Interleukin-2 / biosynthesis*
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Interleukin-2 / genetics
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Interleukin-2 / metabolism
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Lupus Erythematosus, Systemic / enzymology*
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / pathology
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Middle Aged
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Phosphoprotein Phosphatases / biosynthesis
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / physiology*
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Promoter Regions, Genetic
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Protein Binding
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Protein Phosphatase 2
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Proto-Oncogene Proteins c-fos / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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T-Lymphocyte Subsets / enzymology
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Transcription Factor AP-1 / metabolism
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Up-Regulation / physiology
Substances
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Immunoglobulin G
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Interleukin-2
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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RNA, Small Interfering
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Transcription Factor AP-1
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Phosphoprotein Phosphatases
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Protein Phosphatase 2