IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction.
Barlow, Jillian L. PhD a,*,*; Peel, Samantha PhD b,*; Fox, Jane PhD b,*; Panova, Veera MRes a; Hardman, Clare S. BSc a; Camelo, Ana PhD a; Bucks, Christine PhD c; Wu, Xiaoying MD c; Kane, Colleen M. PhD c; Neill, Daniel R. PhD d; Flynn, Robin J. PhD e; Sayers, Ian PhD b; Hall, Ian P. DM b; McKenzie, Andrew N.J. PhD a
[Miscellaneous Article]
Journal of Allergy & Clinical Immunology.
132(4):933-941, October 2013.
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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.
(C) 2013Elsevier, Inc.