IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma

J Allergy Clin Immunol. 2013 Sep;132(3):676-685.e13. doi: 10.1016/j.jaci.2013.04.012. Epub 2013 Jun 4.


Background: TH2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown.

Objective: We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA.

Methods: IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified.

Results: Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA.

Conclusion: IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.

Keywords: AAD; AHR; Airway hyperresponsiveness; Allergic airways disease; Asthma; BAL; Bronchoalveolar lavage; EB; Endobronchial biopsy; HDM; House dust mite; IL-33; RBM; Reticular basement membrane; STRA; Severe therapy-resistant asthma; airway remodeling; pediatric; steroid resistance; therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Airway Remodeling* / physiology
  • Animals
  • Animals, Newborn
  • Anti-Inflammatory Agents / therapeutic use
  • Asthma / drug therapy
  • Asthma / immunology
  • Asthma / pathology*
  • Bronchial Hyperreactivity / immunology*
  • Bronchial Hyperreactivity / pathology
  • Budesonide / therapeutic use
  • Child
  • Collagen / immunology
  • Drug Resistance
  • Female
  • Glucocorticoids / therapeutic use
  • Humans
  • Interleukin-13 / immunology
  • Interleukin-33
  • Interleukins / administration & dosage
  • Interleukins / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pyroglyphidae / immunology


  • Anti-Inflammatory Agents
  • Glucocorticoids
  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukins
  • Budesonide
  • Collagen