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).
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Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, 1222 VSRH, 2201 Capers Avenue, Nashville, TN 37212, USA.
Bright
J J
JJ
Sriram
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S
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