| First Author | Clark JM | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 9 | Pages | e24504 |
| PubMed ID | 21915344 | Mgi Jnum | J:177696 |
| Mgi Id | MGI:5295836 | Doi | 10.1371/journal.pone.0024504 |
| Citation | Clark JM, et al. (2011) Inhibitor of kappa B epsilon (IkappaBepsilon) is a non-redundant regulator of c-Rel-dependent gene expression in murine T and B cells. PLoS One 6(9):e24504 |
| abstractText | Inhibitors of kappa B (IkappaBs) -alpha, -beta and -epsilon effect selective regulation of specific nuclear factor of kappa B (NF-kappaB) 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 IkappaBs but activation only of subsets of NF-kappaB-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-alpha (TNF) inhibits IL-2 gene expression at the level of transcription through suppressive effects on NF-kappaB, AP-1 and NFAT transcription factor expression and function. Selective upregulation of IkappaBepsilon 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. IkappaBepsilon associated with newly synthesised c-Rel in activated cells and, in contrast to IkappaBalpha and -beta, showed enhanced association with p65/c-Rel in TNF-treated cells relative to controls. Studies in IkappaBepsilon-deficient mice revealed that basal nuclear expression and nuclear translocation of c-Rel at early time-points of receptor ligation were higher in IkappaBepsilon-/- T and B cells, compared to wild-type. IkappaBepsilon-/- mice exhibited increased lymph node cellularity and enhanced basal thymidine incorporation by lymphoid cells ex vivo. IkappaBepsilon-/- T cell blasts were primed for IL-2 expression, relative to wild-type. IkappaBepsilon-/- 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 IkappaBalpha expression in IkappaBepsilon-/- B cells. The data imply that regulation of these c-Rel-dependent lymphoid responses is a non-redundant function of IkappaBepsilon. |
