Abstract
Damaging inflammation arising from autoimmune pathology and septic responses results in severe cases of disease. In both instances, anti-inflammatory compounds are used to limit the excessive or deregulated cytokine responses. We used a model of robust T cell stimulation to identify new proteins involved in triggering a cytokine storm. A comparative proteomic mining approach revealed the differential mapping of Raf kinase inhibitory protein after T cell recall in vivo. Treatment with locostatin, an Raf kinase inhibitory protein inhibitor, induced T cell anergy by blocking cytokine production after Ag recall. This was associated with a reduction in Erk phosphorylation. Importantly, in vivo treatment with locostatin profoundly inhibited TNF-alpha production upon triggering the Ag-specific T cells. This effect was not limited to a murine model because locostatin efficiently inhibited cytokine secretion by human lymphocytes. Therefore, locostatin should be a useful therapeutic to control inflammation, sepsis, and autoimmune diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Blotting, Western
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Chromatography, Liquid
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Clonal Anergy
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Cytokines / drug effects*
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Electrophoresis, Polyacrylamide Gel
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flow Cytometry
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Fluorescent Antibody Technique
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Humans
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Oxazolidinones / pharmacology*
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Phosphatidylethanolamine Binding Protein / biosynthesis
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Phosphatidylethanolamine Binding Protein / drug effects*
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Phosphorylation
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Proteomics
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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Tandem Mass Spectrometry
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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Anti-Inflammatory Agents
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Cytokines
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Oxazolidinones
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Phosphatidylethanolamine Binding Protein
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Tumor Necrosis Factor-alpha
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locostatin
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Extracellular Signal-Regulated MAP Kinases