title: Tumour-necrosis-factor-receptor-associated factor 6, NF-kappaB-inducing kinase and IkappaB kinases mediate IgE isotype switching in response to CD40.
abstract: The process of IgE switching requires the prior transcription of the unrearranged Cepsilon gene, which leads to its recombination with the VDJ region. The activation of NF-kappaB by CD40 is a key process in facilitating this transcription by promoting the activation of the Cepsilon promoter. The present study explores the uncharacterized signalling pathways employed by CD40 in activating NF-kappaB by the overexpression of genes encoding wild-type and dominant-negative forms of the signalling components tumour-necrosis-factor-receptor-associated factor 6 (TRAF-6), NF-kappaB-inducing kinase (NIK), IkappaB kinase (IKK)-1 and IKK-2 in the BJAB B-cell line. The overexpression of TRAF-6 or NIK was sufficient to activate NF-kappaB and the Cepsilon promoter, whereas their dominant-negative counterparts decreased the ability of CD40 to activate NF-kappaB and the Cepsilon promoter. The overexpression of wild-type IKK-1 or IKK-2 seemed to cause toxic effects on the cells, whereas the dominant-negative forms were selective in their blockade of NF-kappaB and the Cepsilon promoter. These results suggest that CD40 employs TRAF-6, which presumably recruits NIK, which in turn employs IKK-1/IKK-2 to activate NF-kappaB and the Cepsilon promoter, the prologue to IgE switching. Thus the findings define a crucially important pathway in the generation of allergic states.
authors.affiliation: Department of Pharmacology, University College Dublin, Foster Avenue, Blackrock, Co. Dublin, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: Brady
authors.forename: S
authors.initials: S
authors.lastname: Fitzgerald
authors.forename: P N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D001483:Base Sequence; D019013:CD40 Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D019013:CD40 Antigens; D002352:Carrier Proteins; D017931:DNA Primers; D020672:I-kappa B Proteins; D007073:Immunoglobulin E; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase