Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction.
In this study, we explored the therapeutic targets of the glycosylation processing inhibitor, castanospermine (CAST), in murine passive transfer experimental autoimmune encephalomyelitis (EAE), a model disease of multiple sclerosis. By using lymphocytic-endothelial adhesion and transmigration assays, FACScan and Western blotting, we defined the effects of CAST on expression, function and signal transduction of glycoproteins crucial in the pathophysiology of this disease. CAST prevented clinical signs of EAE and completely inhibited inflammatory CNS infiltrates associated with this disease. Here, we showed that CAST blocks antigen-induced lymphocytic activation and clonal expansion in a dose-dependent manner. Importantly, we observed that CAST strongly impairs IL-2-induced signal transduction of the IL-2 receptor. In contrast, neither expression nor binding ability of the IL-2 receptor was affected by this drug. In addition, we were able to exclude major effects of CAST on expression and function of different glycoproteins important in antigen presentation as well as lymphocytic-endothelial adhesion and transmigration. In conclusion, CAST strongly interferes in the signal transduction of the IL-2 receptor. This could explain both inhibitory effects of CAST in clonal T cell expansion and development of transfer EAE. This relatively selective pharmacological effect of CAST highlights its potential as a novel immunomodulatory approach in multiple sclerosis.
Walter
Silke
S
Department of Neurology, University of Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. silke.walter@med.uni-goettingen.de
Fassbender
Klaus
K
Gulbins
Erich
E
Liu
Yang
Y
Rieschel
Monika
M
Herten
Monika
M
Bertsch
Thomas
T
Engelhardt
Britta
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006031:Glycosylation / Q000187:drug effects*; D007212:Indolizines / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology; D054836:Indolizidines
D004791:Enzyme Inhibitors; D007212:Indolizines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; C037806:castanospermine; D054836:Indolizidines