De novo synthesized RelB mediates TNF-induced up-regulation of the human polymeric Ig receptor.
Secretory Abs, which operate in a principally noninflammatory fashion, constitute the first line of acquired immune defense of mucosal surfaces. Such Abs are generated by polymeric Ig receptor (pIgR)-mediated export of dimeric IgA and pentameric IgM. TNF activates a proinflammatory gene repertoire in mucosal epithelial cells and also enhances pIgR expression. In this study we show that TNF-induced up-regulation of the human pIgR critically depends on an NF-kappa B site and flanking sequences within a 204-bp region of the first intron in the pIgR gene, a region largely overlapping with a recently characterized IL-4-responsive enhancer. The intronic NF-kappa B site was rapidly bound by NF-kappa B p65/p50 heterodimers present in nuclear extracts after TNF treatment of HT-29 cells, but a more delayed binding of RelB agreed better with the slow, protein synthesis-dependent, transcriptional activation of the pIgR gene. Overexpression of NF-kappa B p65 caused transient up-regulation of a pIgR-derived reporter gene, whereas overexpression of RelB showed a stronger and more sustained effect. Finally, we demonstrated that inhibition of endogenous RelB by RNA interference severely reduced the TNF responsiveness of our pIgR-derived reporter gene. Thus, TNF-induced signaling pathways required for up-regulated pIgR expression appear to differ from those of the proinflammatory gene repertoire.
Schjerven
Hilde
H
Laboratory for Immunohistochemistry and Immunopathology, Institute and Department of Pathology, Rikshospitalet University Hospital, Oslo, Norway.
Tran
Thien N
TN
Brandtzaeg
Per
P
Johansen
Finn-Eirik
FE
D000230:Adenocarcinoma / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology; D019281:Dimerization; D004742:Enhancer Elements, Genetic / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D034622:RNA Interference; D019056:Receptors, Polymeric Immunoglobulin / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D019056:Receptors, Polymeric Immunoglobulin; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB