title: IκBε is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner.
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.
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Bryce N
authors.initials: BN
authors.lastname: Alves
authors.forename: Rachel
authors.initials: R
authors.lastname: Tsui
authors.forename: Jonathan
authors.initials: J
authors.lastname: Almaden
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Shokhirev
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis-Turak
authors.forename: Jessica
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Harry
authors.initials: H
authors.lastname: Birnbaum
authors.forename: Julia
authors.initials: J
authors.lastname: Ponomarenko
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000465:Algorithms; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological / Q000187:drug effects; D005434:Flow Cytometry; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D055503:Protein Multimerization / Q000276:immunology; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051996:Transcription Factor RelA / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; C496566:Ikbke protein, mouse