<h3>Background</h3> 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 (<i>IL1RL1</i> and <i>IL33</i>) have been significantly associated with asthma in large-cohort genome-wide association studies. <h3>Objective</h3> 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. <h3>Methods</h3> IL-25 receptor–deficient <i>(Il17rb</i><sup>−/−</sup><i>)</i>, IL-33 receptor–deficient (ST2, Il1rl1<sup>−/−</sup>), and double-deficient <i>(Il17rb</i><sup>−/−</sup><i>Il1rl1</i><sup>−/−</sup><i>)</i> mice were analyzed in models of allergic asthma. Microarrays, an <i>ex vivo</i> lung slice airway contraction model, and <i>Il13</i><sup>+/eGFP</sup> mice were then used to identify specific effects of IL-25 and IL-33 administration. <h3>Results</h3> Comparison of IL-25 and IL-33 pathway–deficient mice demonstrates that IL-33 signaling plays a more important <i>in vivo</i> role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction <i>ex vivo</i> 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 <i>Il13</i><sup>+/eGFP</sup> 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 <i>in vivo</i> because IL-33 is more rapidly expressed and released in comparison with IL-25. <h3>Conclusion</h3> 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.

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