Tumour-necrosis-factor-receptor-associated factor 6, NF-kappa B-inducing kinase and I kappa B kinases mediate IgE isotype switching in response to CD40
K. Brady et al., Tumour-necrosis-factor-receptor-associated factor 6, NF-kappa B-inducing kinase and I kappa B kinases mediate IgE isotype switching in response to CD40, BIOCHEM J, 350, 2000, pp. 735-740
The process of IgE switching requires the prior transcription of the unrear
ranged C epsilon gene, which leads to its recombination with the VDJ region
. The activation of NF-kappa B by CD40 is a key process in facilitating thi
s transcription by promoting the activation of the C epsilon promoter. The
present study explores the uncharacterized signalling pathways employed by
CD40 in activating NF-kappa B by the overexpression of genes encoding wildt
ype and dominant-negative forms of the signalling components tumour-necrosi
s-factor-receptor-associated factor 6 (TRAF-6), NF-kappa B-inducing kinase
(NIK), I kappa B kinase (IKK)-1 and IKK-2 in the BJAB B-cell line. The over
expression of TRAF-6 or NIK was sufficient to activate NF-kappa B and the C
epsilon promoter, whereas their dominant-negative counterparts decreased t
he ability of CD40 to activate NF-kappa B and the C epsilon promoter. The o
verexpression of wild-type IKK-1 or 1KK-2 seemed to cause toxic effects on
the cells, whereas the dominant-negative forms were selective in their bloc
kade of NF-kappa B and the C epsilon promoter. These results suggest that C
D40 employs TRAF-6, which presumably recruits NIK, which in turn employs IK
K-1/IKK-2 to activate NF-kappa B and the C epsilon promoter, the prologue t
o IgE switching. Thus the findings define a crucially important pathway in
the generation of allergic states.