IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction
IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction
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DOI：
10.1016/j.jaci.2013.05.012
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发表时间：
2013-10-01
影响因子：
14.2
通讯作者：
McKenzie, Andrew N. J.
中科院分区：
文献类型：
--
作者：
Barlow, Jillian L.;Peel, Samantha;McKenzie, Andrew N. J.
背景资料：IL-25和IL-33属于不同的细胞因子家族，但实验小鼠研究表明它们在2型免疫中的免疫功能几乎完全重叠。然而，只有IL-33通路中的多态性目的：我们试图确定IL-25和IL-33在肺中的不同通路，这可能为深入了解它们在哮喘发病机制中的作用和治疗干预的潜力提供线索。方法：在过敏性哮喘模型中分析了IL-25受体缺陷型（Il 17 rb（-/-））、IL-33受体缺陷型（ST 2、Il 1 rl 1（-/-））和双重缺陷型（Il 17 rb（-/-）Il 1 rl 1（-/-））小鼠。微阵列，离体肺切片气道收缩模型，和IL 13 1/eGFP小鼠，然后被用来确定IL-25和IL-33 administration.Results的具体效果：IL-25和IL-33通路缺陷小鼠的比较表明，IL-33信号转导在气道高反应性比IL-25在体内起着更重要的作用。此外，乙酰甲胆碱诱导的离体气道收缩在用IL-33而不是IL-25处理后增加。这取决于IL-33受体和2型细胞因子的表达。用IL 13 1/eGFP小鼠的共聚焦研究显示IL-33更有效地诱导产生IL-13的2型先天淋巴细胞的扩增，与气道收缩相关。结论：IL-33通过刺激产生IL-13的2型先天性淋巴细胞迅速扩增而在快速诱导气道收缩中起重要作用，而IL-25诱导的反应较慢且较弱。
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 1/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 1/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.