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.
Highlights
Members of the nuclear factor of kappa B (NF-kB) transcription factor family, p50, p52, p65 (RelA), c-Rel and RelB, are maintained as inactive homo- or heterodimers in the cytoplasm by inhibitors of kappa B (IkBs)
When studying effects of tumour necrosis factor-a (TNF) on T cell function, we observed that pre-treatment of mouse T cell hybridoma 11A2 with picomolar concentrations of TNF suppressed induction of secreted IL-2 protein by more than 90%, relative to untreated cells
Inhibition of IL-2 induction was at the level of mRNA expression, as determined by ribonuclease protection assay, peak expression of IL2 mRNA being reduced by at least 90% in TNF-treated as compared to control cells, for all stimuli (Figure 1B)
Summary
Members of the nuclear factor of kappa B (NF-kB) transcription factor family, p50, p52, p65 (RelA), c-Rel and RelB, are maintained as inactive homo- or heterodimers in the cytoplasm by inhibitors of kappa B (IkBs). The RHDs contain dimerisation, nuclear localisation and DNAbinding regions, and c-Rel, p65 and RelB, but not p50 and p52, have transactivation domains which confer transcriptional activity. IkB degradation permits nuclear translocation of NF-kB and induction of genes responsible for many cellular responses including inflammation, survival and differentiation [4,5,6]. Activated NF-kB itself induces resynthesis of all three IkBs. How, are signal-, cell- and subunit-specific regulation of NFkB dimers and their target genes brought about? Studies suggest that the necessary specificity may be achieved via differential expression - in space and time - of IkB isoforms. The rate of degradation and resynthesis of each isoform may vary with stimulus and cell-type [7], and according to the differentiation status of a cell. IkBe differs from IkBs -a and -b structurally [8]; and IkBs differ from one another in preferential
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