Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity
| Autor: | 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 |
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| Rok vydání: | 2014 |
| Předmět: |
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 |
| Zdroj: | The Journal of Immunology. 193:5294-5305 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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