Abstract
Activation of antigen presenting cells through the interaction of CD40 with its ligand is a critical co-stimulatory signal for IL-12 production and Th1 differentiation. Tyrphostins are organic molecules that inhibit the phosphorylation of protein tyrosine kinases. We show that tyrphostin A1 inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells. Our data also show that tyrphostin A1 blocks CD40L-induced translocation of NF-kappaB to the nucleus, and reduces the activation of IL-12 p40 gene. In vivo therapy with A1 leads to decrease in generation of myelin basic protein (MBP) specific encephalitogenic T cells. In addition, treatment of SJL/J mice with A1 results in attenuation of experimental allergic encephalomyelitis (EAE).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantigens / immunology
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CD40 Antigens / metabolism*
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CD40 Ligand / pharmacology
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Cell Division / immunology
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Cell Nucleus / metabolism
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Cells, Cultured
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Female
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Gene Expression / drug effects
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Gene Expression / immunology
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Interferon-gamma / metabolism
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-12 / metabolism*
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Lymph Nodes / cytology
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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Mice, Inbred Strains
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Myelin Basic Protein / immunology
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Promoter Regions, Genetic / immunology
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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Solubility
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Th1 Cells / cytology
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Tyrphostins / pharmacology*
Substances
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Autoantigens
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CD40 Antigens
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Myelin Basic Protein
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NF-kappa B
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Tyrphostins
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CD40 Ligand
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Interleukin-12
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Interferon-gamma