Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: role of STAT6 in cell type-specific delayed transcriptional response

J Immunol. 2000 Oct 1;165(7):3898-906. doi: 10.4049/jimmunol.165.7.3898.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Binding Sites / immunology
  • COS Cells
  • Chlorocebus aethiops
  • 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
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / physiology*
  • Introns / immunology
  • Kinetics
  • Luciferases / antagonists & inhibitors
  • Luciferases / genetics
  • Molecular Sequence Data
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / biosynthesis
  • Receptors, Polymeric Immunoglobulin / antagonists & inhibitors
  • Receptors, Polymeric Immunoglobulin / biosynthesis*
  • Receptors, Polymeric Immunoglobulin / genetics
  • Regulatory Sequences, Nucleic Acid / immunology
  • Response Elements / immunology*
  • STAT6 Transcription Factor
  • Time Factors
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transcription, Genetic / immunology*
  • Up-Regulation / drug effects
  • Up-Regulation / immunology*

Substances

  • RNA, Messenger
  • Receptors, Polymeric Immunoglobulin
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Trans-Activators
  • Interleukin-4
  • Cycloheximide
  • Luciferases

Associated data

  • GENBANK/AJ276452