Tumour-necrosis-factor-receptor-associated factor 6, NF-κB-inducing kinase and IκB kinases mediate IgE isotype switching in response to CD40

The process of IgE switching requires the prior transcription of the unrearranged 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 this 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 wildtype and dominant-negative forms of the signalling components tumour-necrosis-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 overexpression of TRAF-6 or NIK was sufficient to activate NF-kappa B and the C epsilon promoter, whereas their dominant-negative counterparts decreased the ability of CD40 to activate NF-kappa B and the C epsilon promoter. The overexpression 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 blockade of NF-kappa B and the C epsilon promoter. These results suggest that CD40 employs TRAF-6, which presumably recruits NIK, which in turn employs IKK-1/IKK-2 to activate NF-kappa B and the C epsilon promoter, the prologue to IgE switching. Thus the findings define a crucially important pathway in the generation of allergic states.