title: Hepatocyte NF-1 and STAT6 cooperate with additional DNA-binding factors to activate transcription of the human polymeric Ig receptor gene in response to IL-4.
abstract: Secretory IgA and IgM, which protect the mucosal surfaces, are generated by selective transport of locally produced polymeric (p)Igs through the epithelial barrier by the pIgR. The expression of this receptor, and hence the generation of secretory Igs, is modulated by numerous extracellular factors. We have previously identified a STAT6 site in intron 1 of the human pIgR gene that is required for the slow and de novo protein synthesis-dependent IL-4-mediated transcriptional activation of the gene. In this study, we show that this intronic IL-4-responsive enhancer is confined to a 250-bp region that is highly conserved in the murine pIgR gene. The enhancer was dependent on the cooperation between the STAT6 site and at least four additional DNA elements. EMSA experiments demonstrated binding by hepatocyte NF-1 to one of these DNA elements. Extensive overlap in the tissue distribution of hepatocyte NF-1 and pIgR suggests that this transcription factor contributes to tissue-specific pIgR expression. Changing the helical phase between the STAT6 site and downstream DNA elements greatly reduced the strength of the IL-4 response, suggesting that the precise organization of this enhancer is important for its proper function. Thus, several transcription factors cooperate in this enhanceosome to mediate IL-4 responsiveness in HT-29 epithelial cells.
authors.affiliation: Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology, University of Oslo, Rikshospitalet, Oslo, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Schjerven
authors.forename: Per
authors.initials: P
authors.lastname: Brandtzaeg
authors.forename: Finn-Eirik
authors.initials: FE
authors.lastname: Johansen
mesh_terms: D001482:Base Composition / Q000276:immunology; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology; D021901:DNA, Intergenic / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000276:immunology; D019073:HT29 Cells; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology*; D007438:Introns / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D019056:Receptors, Polymeric Immunoglobulin / Q000235:genetics* / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology*; D014162:Transfection
chemical_list: D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D019056:Receptors, Polymeric Immunoglobulin; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D015847:Interleukin-4