title: Inhibitor of kappa B epsilon (IκBε) is a non-redundant regulator of c-Rel-dependent gene expression in murine T and B cells.
abstract: Inhibitors of kappa B (IκBs) -α, -β and -ε effect selective regulation of specific nuclear factor of kappa B (NF-κB) dimers according to cell lineage, differentiation state or stimulus, in a manner that is not yet precisely defined. Lymphocyte antigen receptor ligation leads to degradation of all three IκBs but activation only of subsets of NF-κB-dependent genes, including those regulated by c-Rel, such as anti-apoptotic CD40 and BAFF-R on B cells, and interleukin-2 (IL-2) in T cells. We report that pre-culture of a mouse T cell line with tumour necrosis factor-α (TNF) inhibits IL-2 gene expression at the level of transcription through suppressive effects on NF-κB, AP-1 and NFAT transcription factor expression and function. Selective upregulation of IκBε and suppressed nuclear translocation of c-Rel were very marked in TNF-treated, compared to control cells, whether activated via T cell receptor (TCR) pathway or TNF receptor. IκBε associated with newly synthesised c-Rel in activated cells and, in contrast to IκBα and -β, showed enhanced association with p65/c-Rel in TNF-treated cells relative to controls. Studies in IκBε-deficient mice revealed that basal nuclear expression and nuclear translocation of c-Rel at early time-points of receptor ligation were higher in IκBε-/- T and B cells, compared to wild-type. IκBε-/- mice exhibited increased lymph node cellularity and enhanced basal thymidine incorporation by lymphoid cells ex vivo. IκBε-/- T cell blasts were primed for IL-2 expression, relative to wild-type. IκBε-/- splenic B cells showed enhanced survival ex vivo, compared to wild-type, and survival correlated with basal expression of CD40 and induced expression of CD40 and BAFF-R. Enhanced basal nuclear translocation of c-Rel, and upregulation of BAFF-R and CD40 occurred despite increased IκBα expression in IκBε-/- B cells. The data imply that regulation of these c-Rel-dependent lymphoid responses is a non-redundant function of IκBε.
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Division of Immunology, Infection and Inflammatory Diseases, School of Medicine, King's College London, University of London, London, United Kingdom.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Clark
authors.forename: Karolina
authors.initials: K
authors.lastname: Aleksiyadis
authors.forename: Alex
authors.initials: A
authors.lastname: Martin
authors.forename: Kay
authors.initials: K
authors.lastname: McNamee
authors.forename: Tharsana
authors.initials: T
authors.lastname: Tharmalingam
authors.forename: Richard O
authors.initials: RO
authors.lastname: Williams
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mémet
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D020569:Proto-Oncogene Proteins c-rel; D051550:I-kappa B Kinase; C496566:Ikbke protein, mouse