Glycosylation processing inhibition by castanospermine prevents experimental autoimmune encephalomyelitis by interference with IL-2 receptor signal transduction
Abstract
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.
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Several data indicate the improving effect of iminosugars on EAE.
“but several data indicate the improving effect of iminosugars on EAE [451,452,453].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [452]
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- Authors
- Walter, S., Fassbender, K., Gulbins, E., Liu, Y., Rieschel, M., Herten, M., Bertsch, T., & Engelhardt, B.
- Affiliations
- University of Göttingen (DE)
- St. Jude Children's Research Hospital (US)
- Max Planck Society (DE)
- Heinrich Heine University Düsseldorf (DE)
- Heidelberg University (DE)
- Corresponding author
- Walter, Silke
- ORCID
- Venue
- Journal of Neuroimmunology
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 132
- Issue
- 1-2
- Pages
- 1-10
- ISSN
- 0165-5728 (ISSN-L)
- OpenAlex
- W2094801848
- Cited by
- 41
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 1 · 2020: 1 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 1
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroimmunology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- castanospermine, experimental autoimmune encephalomyelitis, multiple sclerosis, interleukin-2 receptor, signal transduction, T cell clonal expansion, lymphocyte transmigration, immunomodulatory therapy
- MeSH terms
- Animals, Cell Adhesion, Cell Movement, Encephalomyelitis, Autoimmune, Experimental, Endothelium, Vascular, Enzyme Inhibitors, Female, Glycosylation, Indolizines, Interleukin-2, Lymphocyte Activation, T-Lymphocytes, Receptors, Interleukin-2, Signal Transduction, Apoptosis, Mice, Indolizidines
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