IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction

J Allergy Clin Immunol. 2013 Oct;132(4):933-41. doi: 10.1016/j.jaci.2013.05.012. Epub 2013 Jun 27.


Background: IL-25 and IL-33 belong to distinct cytokine families, but experimental mouse studies suggest their immunologic functions in type 2 immunity are almost entirely overlapping. However, only polymorphisms in the IL-33 pathway (IL1RL1 and IL33) have been significantly associated with asthma in large-cohort genome-wide association studies.

Objective: We sought to identify distinct pathways for IL-25 and IL-33 in the lung that might provide insight into their roles in asthma pathogenesis and potential for therapeutic intervention.

Methods: IL-25 receptor-deficient (Il17rb(-/-)), IL-33 receptor-deficient (ST2, Il1rl1(-/-)), and double-deficient (Il17rb(-/-)Il1rl1(-/-)) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il13(+/eGFP) mice were then used to identify specific effects of IL-25 and IL-33 administration.

Results: Comparison of IL-25 and IL-33 pathway-deficient mice demonstrates that IL-33 signaling plays a more important in vivo role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction ex vivo increases after treatment with IL-33 but not IL-25. This is dependent on expression of the IL-33 receptor and type 2 cytokines. Confocal studies with Il13(+/eGFP) mice show that IL-33 more potently induces expansion of IL-13-producing type 2 innate lymphoid cells, correlating with airway contraction. This predominance of IL-33 activity is enforced in vivo because IL-33 is more rapidly expressed and released in comparison with IL-25.

Conclusion: Our data demonstrate that IL-33 plays a critical role in the rapid induction of airway contraction by stimulating the prompt expansion of IL-13-producing type 2 innate lymphoid cells, whereas IL-25-induced responses are slower and less potent.

Keywords: AHR; Airways hyperreactivity; BAL; Bronchoalveolar lavage; Cit; Citrine; ICOS; IL-13; IL-25; IL-33; ILC2; Inducible costimulator; Nuocytes; OVA; Ovalbumin; RWP; Ragweed pollen; Tom; Tomato; Type 2 innate lymphoid cells; asthma; contraction; type 2 innate lymphoid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / immunology
  • Asthma / physiopathology*
  • Bronchial Hyperreactivity / immunology*
  • Bronchial Hyperreactivity / physiopathology
  • Humans
  • Interleukin-13 / biosynthesis*
  • Interleukin-33
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Th2 Cells / cytology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism


  • Il33 protein, mouse
  • Interleukin-13
  • Interleukin-33
  • Interleukins
  • Mydgf protein, mouse