ArticleJournal of immunology (Baltimore, Md. : 1950)2014
IκBε is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner.
Article in Journal of immunology (Baltimore, Md. : 1950), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 64 citations in OpenAlex.
- Review
- Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies.Leukemia · 2026Article
- Computational modelling of aggressive B-cell lymphoma.Biochemical Society transactions · 2025Review
- Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.Cell death & disease · 2025Article
- Marginal zone and follicular B cells respond differently to TLR4 and TLR9 stimulation.bioRxiv : the preprint server for biology · 2025Article
- NF-κB: master regulator of cellular responses in health and disease.Immunity & inflammation · 2025Review
- Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Versatile function of NF-ĸB in inflammation and cancer.Experimental hematology & oncology · 2024Review
- NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia.Leukemia · 2024Article
- Article
- Co-imaging of RelA and c-Rel reveals features of NF-κB signaling for ligand discrimination.Cell reports · 2024Article
- Processing stimulus dynamics by the NF-κB network in single cells.Experimental & molecular medicine · 2023Review
- Nuclear factor kappa B expression in non-small cell lung cancer.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Review
- cFLIPCellular & molecular immunology · 2023Article
- Expression of IkappaB Family in the Ovine Liver during Early Pregnancy.Animals : an open access journal from MDPI · 2023Article
- The NF-κB multidimer system model: A knowledge base to explore diverse biological contexts.Science signaling · 2023Review
- Early Pregnancy Regulates Expression of IkappaB Family in Ovine Spleen and Lymph Nodes.International journal of molecular sciences · 2023Article
- Article
- The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells.Frontiers in immunology · 2023Review
- From Antibody Repertoires to Cell-Cell Interactions to Molecular Networks: Bridging Scales in the Germinal Center.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The transcription factor NF-κB is a regulator of inflammatory and adaptive immune responses, yet only IκBα was shown to limit NF-κB activation and inflammatory responses. We investigated another negative feedback regulator, IκBε, in the regulation of B cell proliferation and survival. Loss of IκBε resulted in increased B cell proliferation and survival in response to both antigenic and innate stimulation. NF-κB activity was elevated during late-phase activation, but the dimer composition was stimulus specific. In response to IgM, cRel dimers were elevated in IκBε-deficient cells, yet in response to LPS, RelA dimers also were elevated. The corresponding dimer-specific sequences were found in the promoters of hyperactivated genes. Using a mathematical model of the NF-κB-signaling system in B cells, we demonstrated that kinetic considerations of IκB kinase-signaling input and IκBε's interactions with RelA- and cRel-specific dimers could account for this stimulus specificity. cRel is known to be the key regulator of B cell expansion. We found that the RelA-specific phenotype in LPS-stimulated cells was physiologically relevant: unbiased transcriptome profiling revealed that the inflammatory cytokine IL-6 was hyperactivated in IκBε(-/-) B cells. When IL-6R was blocked, LPS-responsive IκBε(-/-) B cell proliferation was reduced to near wild-type levels. Our results provide novel evidence for a critical role for immune-response functions of IκBε in B cells; it regulates proliferative capacity via at least two mechanisms involving cRel- and RelA-containing NF-κB dimers. This study illustrates the importance of kinetic considerations in understanding the functional specificity of negative-feedback regulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.