CD154 tone sets the signaling pathways and transcriptome generated in model CD40-pluricompetent L3055 Burkitt's lymphoma cells
| Autor: | John R. Arrand, Aristides G. Eliopoulos, Anita Challa, Martin Rowe, Wenbin Wei, Ross Stewart, John Gordon, Richard J. Armitage, Lawrence S. Young |
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| Předmět: |
Antigens
CD40/*immunology Transcription Genetic Cell Survival Immunology CD40 Ligand Gene Expression Signal Transduction/genetics/immunology NF-kappa B/analysis/antagonists & inhibitors/metabolism Transcriptome Cell Line Tumor medicine Burkitt Lymphoma/*genetics Immunology and Allergy Humans CD154 CD40 Antigens Receptor B cell Genetics CD40 CD40 Ligand/*immunology/pharmacology biology Gene Expression Profiling NF-kappa B medicine.disease Phenotype Burkitt Lymphoma Cell biology medicine.anatomical_structure biology.protein Signal transduction Burkitt's lymphoma Signal Transduction |
| Zdroj: | Scopus-Elsevier |
| Popis: | Activated B cells reacting to small amounts of CD40L (CD154) maintain homeostasis by suppressing default apoptosis. Additional outcomes, particularly differentiation, demand higher CD40 occupancy. Here, focusing on survival, we compared changes in the transcriptome of pleiotropically competent, early passage L3055 Burkitt’s lymphoma cells confronted with low (picomolar) and high (nanomolar) concentrations of CD154 to gain insight into how a single receptor sets these distinct phenotypes. Of 267 genes altering transcriptional activity in response to strong CD154 tone, only 25 changed coordinately on low receptor occupancy. Seven of the top nine common up-regulated genes were targets of NF-κB. Direct measurement and functional inhibition of the NF-κB pathway revealed it to be central to a CD40-dependent survival signature. Although the canonical NF-κB axis was engaged by both signaling strengths equally, robust alternative pathway activation was a feature selective to a strong CD40 signal. Discriminatory exploitation of the two separate arms of NF-κB activation may indicate a principle whereby a cell senses and reacts differentially to shifting ligand availability. Identifying components selectively coupling CD40 to each axis could indicate targets for disruption in B cell pathologies underpinned by ectopic and/or hyper-CD154 activity such as neoplasia and some autoimmunities. |
| Databáze: | OpenAIRE |
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