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

Jillian L. Barlow (Lead / Corresponding author), Samantha Peel, Jane Fox, Veera Panova, Clare S. Hardman, Ana Camelo, Christine M. Bucks, Xiaoying Wu, Colleen M. Kane, Daniel Neill, Robin J. Flynn, Ian Sayers, Ian P. Hall, Andrew N. J. McKenzie

Research output: Contribution to journalArticlepeer-review

311 Citations (Scopus)


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-/-/2Il1rl1-/-) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il131+/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 Il131+/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. 
Original languageEnglish
Pages (from-to)933-941
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Issue number4
Publication statusPublished - Oct 2013


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


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