Mechanism of IL-4-Mediated Up-Regulation of the Polymeric Ig Receptor: Role of STAT6 in Cell Type-Specific Delayed Transcriptional Response

• Published in: The Journal of immunology (1950) Vol. 165; no. 7; pp. 3898 - 3906
• Main Authors: Schjerven, Hilde, Brandtzaeg, Per, Johansen, Finn-Eirik
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.2000
• Subjects: Animals; Binding Sites - genetics; Binding Sites - immunology; Cercopithecus aethiops; COS Cells; Cycloheximide - pharmacology; Enhancer Elements, Genetic - immunology; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; Genes, Reporter - immunology; Genetic Vectors - chemical synthesis; Genetic Vectors - immunology; HT29 Cells; Humans; Immunoglobulin receptors; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - physiology; Introns - immunology; Kinetics; Luciferases - antagonists & inhibitors; Luciferases - genetics; Molecular Sequence Data; Receptors, Polymeric Immunoglobulin - antagonists & inhibitors; Receptors, Polymeric Immunoglobulin - biosynthesis; Receptors, Polymeric Immunoglobulin - genetics; Regulatory Sequences, Nucleic Acid - immunology; Response Elements - immunology; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; STAT6 Transcription Factor; Time Factors; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription, Genetic - immunology; Up-Regulation - drug effects; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.7.3898

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.