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We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil\/mast cell stimulation in vitro. Papain induced papain-specific IgE\/IgG1 and lung eosinophilia. Der f 1 induced Der f 1\u2013specific IgG1 and eosinophilia. Although papain-, Der f 1\u2013, and Der p 1\u2013stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor\u2013treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33\u2013deficient mice lacked eosinophilia and had reduced papain-specific IgE\/IgG1. Coadministration of OVA with papain induced OVA-specific IgE\/IgG1, which was reduced in IL-33\u2013deficient mice. We demonstrated IL-33 release, subsequent IL-33\u2013dependent IL-5\/IL-13 release, and activation of T1\/ST2-expressing lineage\u2212CD25+CD44+ innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33\u2013type 2 innate lymphoid cell\u2013IL-5\/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33\u2013responsive innate cells in protease-dependent allergic airway inflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1201212","type":"journal-article","created":{"date-parts":[[2013,4,2]],"date-time":"2013-04-02T01:21:20Z","timestamp":1364865680000},"page":"4489-4499","source":"Crossref","is-referenced-by-count":157,"title":["IL-33\u2013Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen\u2013Induced Allergic Airway Inflammation"],"prefix":"10.1093","volume":"190","author":[{"given":"Seiji","family":"Kamijo","sequence":"first","affiliation":[{"name":"Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine , Tokyo 113-8421,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruna","family":"Takeda","sequence":"additional","affiliation":[{"name":"Atopy (Allergy) Research Center, Juntendo University 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