Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity
| العنوان: | Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity |
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| المؤلفون: | Kerstin Wennhold, Jens Chemitz, Florian Blaschke, Andreas Draube, Michael von Bergwelt-Baildon, Tanja M. Liebig, Udo Holtick, Christof Scheid, Sebastian Theurich, Michael Hallek, Matthias Kochanek, Christian P. Pallasch, Shahram Zoghi, Alexander Shimabukuro-Vornhagen |
| المصدر: | The Journal of Immunology. 193:5294-5305 |
| بيانات النشر: | The American Association of Immunologists, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Simvastatin, Geranylgeranyl Transferase, T-Lymphocytes, medicine.medical_treatment, Primary Cell Culture, Immunology, Protein Prenylation, Mevalonic Acid, Lymphocyte Activation, Geranylgeranylation, Downregulation and upregulation, Atorvastatin, medicine, Humans, Immunology and Allergy, Pyrroles, CD40 Antigens, Antigen Presentation, B-Lymphocytes, Immunity, Cellular, CD40, biology, Immunosuppression, Dendritic Cells, medicine.disease, Transplant rejection, Cytokine, Gene Expression Regulation, Heptanoic Acids, biology.protein, Cancer research, Hydroxymethylglutaryl CoA Reductases, Mevalonate pathway, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Transcriptome, Signal Transduction |
| الوصف: | Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e46334cab79e0e6c16be123c542402ee https://doi.org/10.4049/jimmunol.1203436 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e46334cab79e0e6c16be123c542402ee |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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