Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage, Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice.
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).
Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, 1222 VSRH, 2201 Capers Avenue, Nashville, TN 37212, USA.
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D000818:Animals; D001324:Autoantigens / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002455:Cell Division / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D001324:Autoantigens; D019013:CD40 Antigens; D004676:Myelin Basic Protein; D016328:NF-kappa B; D020032:Tyrphostins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma