Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-κB pathway and promotes lymphomagenesis
| Autor: | Julia Rastelli, Stefano Casola, Klaus Rajewsky, Werner Müller, Leticia Quintanilla-Martinez, Jürgen Ruland, Ursula Zimber-Strobl, Caroline Hojer, Cornelia Hömig-Hölzel, Lothar J. Strobl, Andreas Gewies |
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| Přispěvatelé: | Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Center Munich, German Research Center for Environment and Health, D-81377 Munich, Germany. |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Lymphoma
B-Cell Lymphoma T-Lymphocytes Immunology B-cell receptor Mice Transgenic Lymphocyte Activation Article chemistry.chemical_compound Mice Immune system Antigens CD40 medicine Immunology and Allergy Animals Lymphocyte Count CD40 Antigens B cell Crosses Genetic B-Lymphocytes CD40 biology Kinase NF-kappa B NF-κB Articles Germinal Center TNF Receptor-Associated Factor 2 Cell biology medicine.anatomical_structure chemistry biology.protein Tumor necrosis factor alpha Signal transduction Spleen Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine J. Exp. Med. 205, 1317-1329 (2008) |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T cell–dependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-κB pathway and the mitogen-activated protein kinases Jnk and extracellular signal–regulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas. |
| Databáze: | OpenAIRE |
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