Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: role of STAT6 in cell type-specific delayed transcriptional response.
The polymeric IgR (pIgR) mediates transport of dimeric IgA and pentameric IgM across mucosal epithelia, thereby generating secretory Abs. Its expression is up-regulated at the transcriptional level by IL-4 in HT-29 cells. In this study, we demonstrate that IL-4 mediates up-regulation of human pIgR through a 554-bp IL-4-responsive enhancer in intron 1. Mutation of a binding site for STAT-6 within this region abolished IL-4-induced enhancement, while an adjacent putative C/EBP site was dispensable. IL-4 treatment induced binding of STAT6 to the intronic STAT6 site, but cooperation with nearby upstream and downstream DNA elements was required for IL-4 responsiveness. Furthermore, IL-4-mediated increased transcription of the pIgR-derived enhancer, like the endogenous pIgR gene, required de novo protein synthesis. Interestingly, a conditionally active form of STAT6 sufficed to activate a pIgR-derived enhancer in HT-29 cells, but not in Cos-1 cells, suggesting a requirement for cell type-specific factors. Thus, STAT6 activation mediates a delayed transcriptional enhancement of pIgR by induction of a de novo synthesized protein that cooperates with STAT6 itself bound to its cognate DNA element in intron 1. This mechanism may represent a general strategy for how pleiotropic cytokines elicit cell type-specific transcriptional responses.
Schjerven
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Laboratory for Immunohistochemistry and Immunopathology, Institute of Pathology, University of Oslo, Rikshospitalet, Norway.
Brandtzaeg
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Johansen
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FE
D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003513:Cycloheximide / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007438:Introns / Q000276:immunology; D007700:Kinetics; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000235:genetics; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019056:Receptors, Polymeric Immunoglobulin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D020218:Response Elements / Q000276:immunology*; D050800:STAT6 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D012333:RNA, Messenger; D019056:Receptors, Polymeric Immunoglobulin; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D003513:Cycloheximide; D008156:Luciferases