Ishikawa Yuriko, Yoshimoto Tomohiro, Nakanishi Kenji
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Int Immunol. 2006 Jun;18(6):847-55. doi: 10.1093/intimm/dxl021. Epub 2006 Apr 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 Th1 cells in the presence of IL-12. However, our previous reports clearly demonstrated that IL-18 with IL-2 promotes Th2 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.
人类支气管哮喘的特征为气道高反应性（AHR）、嗜酸性粒细胞性气道炎症、黏液分泌过多以及血清IgE水平升高。白细胞介素18（IL-18）最初被认为在白细胞介素12（IL-12）存在的情况下，可诱导Th1细胞产生Th1相关细胞因子。然而，我们之前的报告清楚地表明，IL-18与IL-2共同作用可促进T细胞和自然杀伤（NK）细胞产生Th2细胞因子。此外，IL-18与IL-3共同刺激嗜碱性粒细胞和肥大细胞产生Th2细胞因子。因此，我们研究了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。经鼻内给予IL-2和IL-18可在未致敏小鼠肺部诱导AHR、黏液分泌过多和嗜酸性粒细胞炎症。CD4⁺ T细胞是这种IL-2加IL-18诱导的支气管哮喘的先决条件，因为CD4⁺ T细胞耗竭或重组激活基因2（Rag-2）缺陷（Rag-2⁻/⁻）小鼠在接受IL-2加IL-18治疗后未发生支气管哮喘。信号转导和转录激活因子6（STAT6）缺陷小鼠和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缺陷小鼠几乎正常发病，这表明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均可同等程度地诱导小鼠胚胎成纤维细胞产生嗜酸性粒细胞趋化因子。然而，只有IL-13阻断可抑制哮喘症状，这表明在该模型中，IL-13而非IL-4大量产生并在支气管哮喘发病机制中起关键作用。由于气道上皮细胞储存大量IL-18，IL-18可能在病原体诱导的支气管哮喘中起关键作用，在这种情况下，病原体刺激上皮细胞产生IL-18而无需IL-12诱导。
