Contribution of IL-18-induced innate T cell activation to airway inflammation with mucus hypersecretion and airway hyperresponsiveness
Contribution of IL-18-induced innate T cell activation to airway inflammation with mucus hypersecretion and airway hyperresponsiveness
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DOI：
10.1093/intimm/dxl021
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Nakanishi, Kenji
中科院分区：
文献类型：
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作者：
Ishikawa, Yuriko;Yoshimoto, Tomohiro;Nakanishi, Kenji
人类支气管哮喘的特征是气道高反应性（AHR）、嗜酸性气道炎症、粘液分泌过多和血清IgE水平高。 IL-18 最初被认为在 IL-12 存在的情况下可从 T(h)1 细胞中诱导 T(h)1 相关细胞因子。然而，我们之前的报告清楚地表明，IL-18 和 IL-2 可以促进 T 细胞和 NK 细胞产生 T(h)2 细胞因子。此外，IL-18 和 IL-3 会刺激嗜碱性粒细胞和肥大细胞产生 Th2 细胞因子。因此，我们检查了 IL-2 和 IL-18 诱导 AHR、气道嗜酸性粒细胞炎症和杯状细胞化生的能力。鼻内给予 IL-2 和 IL-18 会诱导初始小鼠肺部出现 AHR、粘液分泌过多和嗜酸性粒细胞炎症。 CD4(+) T细胞是IL-2加IL-18诱导支气管哮喘的先决条件，因为CD4(+) T细胞耗尽或Rag-2缺陷(Rag-2(-/-))小鼠在IL-2加IL-18治疗后没有发生支气管哮喘。 STAT6(-/-)小鼠和IL-13中和的野生型小鼠均未出现AHR、杯状细胞化生和气道嗜酸性粒细胞炎症，而IL-4(-/-)小鼠几乎正常发育，表明IL-13是主要致病因素，IL-4主要增强AHR和嗜酸性粒细胞炎症的程度。 IL-4 和 IL-13 在小鼠胚胎成纤维细胞中同样诱导嗜酸细胞趋化因子。然而，只有IL-13阻断才能抑制哮喘症状，这表明IL-13而不是IL-4大量产生，并且在该模型中支气管哮喘的发病机制中发挥着关键作用。由于气道上皮细胞储存强大的 IL-18，IL-18 可能与病原体诱导的支气管哮喘密切相关，其中病原体刺激上皮细胞产生 IL-18，而不诱导 IL-12。
Human bronchial asthma is characterized by airway hyperresponsiveness (AHR), eosinophilic airway inflammation, mucus hypersecretion and high serum level of IgE. IL-18 was originally regarded to induce T(h)1-related cytokines from T(h)1 cells in the presence of IL-12. However, our previous reports clearly demonstrated that IL-18 with IL-2 promotes T(h)2 cytokines production from T cells and NK cells. Furthermore, IL-18 with IL-3 stimulates basophils and mast cells to produce Th2 cytokines. Thus, we examined the capacity of IL-2 and IL-18 to induce AHR, airway eosinophilic inflammation and goblet cell metaplasia. Intranasal administration of IL-2 and IL-18 induces AHR, mucus hypersecretion and eosinophilic inflammation in the lungs of naive mice. CD4(+) T cells are prerequisite for this IL-2 plus IL-18-induced bronchial asthma, because CD4(+) T cells-depleted or Rag-2-deficient (Rag-2(-/-)) mice did not develop bronchial asthma after IL-2 plus IL-18 treatment. Both STAT6(-/-) mice and IL-13-neutralized wild-type mice failed to develop AHR, goblet cell metaplasia and airway eosinophilic inflammation, while IL-4(-/-) mice almost normally developed, suggesting that IL-13 is a major causative factor and IL-4 mainly enhances the degree of AHR and eosinophilic inflammation. Both IL-4 and IL-13 equally induce eotaxin in mouse embryonic fibroblasts. However, only IL-13 blockade inhibited asthma symptoms, suggesting that IL-13 but not IL-4 is produced abundantly and plays a critical role in the pathogenesis of bronchial asthma in this model. As airway epithelial cells store robust IL-18, IL-18 might be critically involved in pathogen-induced bronchial asthma, in which pathogens stimulate epithelial cells to produce IL-18 without IL-12 induction.