Volume 6 Supplement 3

Fifth Annual Research Conference: Innovation from Cell to Society

Open Access

IL-13Rα2/AP-1 complex signalling mediates airway epithelial repair without effects on remodeling pathways

  • Jasemine S Yang1,
  • Sima Allahverdian1,
  • Gurpreet K Singhera1,
  • Ruth E MacRedmond1 and
  • Delbert R Dorscheid1
Allergy, Asthma & Clinical Immunology20106(Suppl 3):P27

https://doi.org/10.1186/1710-1492-6-S3-P27

Published: 26 November 2010

Objective/purpose

The airway epithelium serves as a physical defense barrier to the external environment for the underlying tissue and suffers frequent injury. The response to injury is inflammation followed by debris clearance and repair. Although IL-13 is known to be a key cytokine in mediating inflammatory and remodeling responses via signal transducer and activator of transcription 6 (STAT6) and early growth response protein 1 (Egr1), our laboratory has demonstrated that IL-13 is critical to airway epithelial repair via the release of heparin-binding epidermal growth factor (HB-EGF) and activation of epidermal growth factor receptor (EGFR). IL-13 signals through two receptors, IL-13Rα1/IL-4R and IL-13Rα2. IL-13Rα2 has previously been thought to act exclusively as a decoy receptor, however our findings show that IL-13Rα2 can act as a signaling receptor and is involved in mediating airway epithelial repair. Differential signaling via IL-13Rα1 or IL-13Rα2 may determine a remodeling versus repair response to injury in airway epithelium.

Methods

IL-13Rα1 and IL-13Rα2 functions were disrupted in Human Airway Epithelial (1HAEo-) cells using specific IL-13Rα1 and IL-13Rα2 blocking antibodies and small interfering RNAs (siRNAs). 1HAEo- cells were also transfected with activator protein 1 (AP-1) specific and scramble siRNA. Following specific antibody blocking or siRNA transfection, 1HAEo- cells were either stimulated with IL-13 (10 ng/ml) or mechanically injured. Supernatants and protein lysates were collected at different time points. Expressions of phospho-STAT6, STAT6, Egr1, and AP-1 were detected via Western blotting, while HB-EGF release in supernatants was quantified using ELISA. Furthermore, AP-1 activity in 1HAEo- cells after IL-13 stimulation or mechanical injury was measured using an AP-1-luciferase assay.

Findings

IL-13 stimulation resulted in upregulation of phospho-STAT6, Egr1 and AP-1 expression. AP-1 expression correlated with activity as determined by AP-1 luciferase assay. Following mechanical injury, the expression of phospho-STAT6 and Egr1 was inhibited when IL-13Rα1 function was disrupted, while induction of AP-1 expression is unchanged. In contrast, when IL-13Rα2 function was disrupted, HB-EGF and AP-1 expression was inhibited while STAT6/Egr1 signaling remains intact. Gene silencing of AP-1 had no effect on phospho-STAT6 expression in response to injury, however HB-EGF expression was significantly inhibited compared to scramble siRNA treated cells.

Deliverables

Our data indicates that IL-13 mediates repair of airway epithelial cells via IL-13Rα2 and AP-1, while remodeling responses downstream of STAT-6 and EGR-1 are signaled via IL-13 Rα1.

Relevance

Strategies directed towards augmentation of the IL-13Rα2/AP-1 pathway may lead to novel therapies which target the dysfunctional repair phenotype in asthmatic epithelium without adverse effects on airway remodeling.

Authors’ Affiliations

(1)
UBC James Hogg Research Centre, Providence Heart + Lung Institute, St. Paul's Hospital and Faculty of Medicine, University of British Columbia

Copyright

© Yang et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.

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