Endogenously expressed IL-13Rα2 attenuates IL-13-mediated responses but does not activate signaling in human lung fibroblasts

J Immunol. 2014 Jul 1;193(1):111-9. doi: 10.4049/jimmunol.1301761. Epub 2014 May 30.

Abstract

IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas IL-13Rα1/IL-4Rα engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Rα2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Rα1/IL-4Rα complex but does not interact with IL-13Rα2. Idiopathic pulmonary fibrosis is a progressive and generally fatal parenchymal lung disease of unknown etiology with no current pharmacologic treatment options that substantially prolong survival. Preclinical models of fibrotic diseases have implicated IL-13 activity on multiple cell types, including macrophages and fibroblasts, in initiating and perpetuating pathological fibrosis. In this study, we show that IL-13, IL-4, IL-13Rα2, and IL-13-inducible target genes are expressed at significantly elevated levels in lung tissue from patients with idiopathic pulmonary fibrosis compared with control lung tissue. IL-4 and IL-13 induce virtually identical transcriptional responses in human monocytes, macrophages, and lung fibroblasts. IL-13Rα2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-α via a STAT6-independent mechanism. Endogenously expressed IL-13Rα2 decreases, but does not abolish, sensitivity of lung fibroblasts to IL-13 and does not affect sensitivity to IL-4. Genome-wide transcriptional analyses of lung fibroblasts stimulated with IL-13 in the presence of Abs that selectively block interactions of IL-13 with IL-13Rα1/IL-4Rα or IL-13Rα2 show that endogenously expressed IL-13Rα2 does not activate any unique IL-13-mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.

Publication types

  • Clinical Trial

MeSH terms

  • Female
  • Fibroblasts / immunology*
  • Fibroblasts / pathology
  • Gene Expression Regulation / immunology*
  • Genome-Wide Association Study
  • Humans
  • Idiopathic Pulmonary Fibrosis / immunology*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Interleukin-13 / immunology*
  • Interleukin-13 Receptor alpha1 Subunit / immunology
  • Interleukin-13 Receptor alpha2 Subunit / immunology*
  • Interleukin-4 / immunology
  • Interleukin-4 Receptor alpha Subunit / immunology
  • Lung / immunology*
  • Lung / pathology
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Monocytes / immunology
  • Monocytes / pathology
  • STAT6 Transcription Factor / immunology
  • Signal Transduction / immunology*
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • IL13RA1 protein, human
  • IL4 protein, human
  • IL4R protein, human
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • Interleukin-13 Receptor alpha2 Subunit
  • Interleukin-4 Receptor alpha Subunit
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Tumor Necrosis Factor-alpha
  • interleukin-13, human
  • Interleukin-4

Associated data

  • GEO/GSE47527
  • GEO/GSE47538
  • GEO/GSE47542