Kuperman Douglas A, Huang Xiaozhu, Koth Laura L, Chang Grace H, Dolganov Gregory M, Zhu Zhou, Elias Jack A, Sheppard Dean, Erle David J
Lung Biology Center, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, California, USA.
Nat Med. 2002 Aug;8(8):885-9. doi: 10.1038/nm734. Epub 2002 Jul 1.
Asthma is an increasingly common disease that remains poorly understood and difficult to manage. This disease is characterized by airway hyperreactivity (AHR, defined by exaggerated airflow obstruction in response to bronchoconstrictors), mucus overproduction and chronic eosinophilic inflammation. AHR and mucus overproduction are consistently linked to asthma symptoms and morbidity. Asthma is mediated by Th2 lymphocytes, which produce a limited repertoire of cytokines, including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. Although each of these cytokines has been implicated in asthma, IL-13 is now thought to be especially critical. In animal models of allergic asthma, blockade of IL-13 markedly inhibits allergen-induced AHR, mucus production and eosinophilia. Furthermore, IL-13 delivery to the airway causes all of these effects. IL-13 is thus both necessary and sufficient for experimental models of asthma. However, the IL-13-responsive cells causing these effects have not been identified. Here we show that mice lacking signal transducer and activator of transcription 6 (STAT6) were protected from all pulmonary effects of IL-13. Reconstitution of STAT6 only in epithelial cells was sufficient for IL-13-induced AHR and mucus production in the absence of inflammation, fibrosis or other lung pathology. These results demonstrate the importance of direct effects of IL-13 on epithelial cells in causing two central features of asthma.
哮喘是一种日益常见的疾病，目前人们对其了解甚少且难以控制。这种疾病的特征是气道高反应性（AHR，定义为对支气管收缩剂反应时气流阻塞过度）、黏液过度分泌和慢性嗜酸性粒细胞炎症。AHR和黏液过度分泌一直与哮喘症状及发病率相关。哮喘由Th2淋巴细胞介导，Th2淋巴细胞产生有限种类的细胞因子，包括白细胞介素-4（IL-4）、IL-5、IL-9和IL-13。尽管这些细胞因子均与哮喘有关，但现在认为IL-13尤为关键。在过敏性哮喘动物模型中，阻断IL-13可显著抑制变应原诱导的AHR、黏液产生和嗜酸性粒细胞增多。此外，将IL-13输送至气道会引发所有这些效应。因此，IL-13对于哮喘实验模型既是必需的也是充分的。然而，导致这些效应的IL-13反应性细胞尚未得到鉴定。在此我们表明，缺乏信号转导和转录激活因子6（STAT6）的小鼠对IL-13的所有肺部效应具有抵抗力。仅在上皮细胞中重建STAT6就足以在无炎症、纤维化或其他肺部病变的情况下引发IL-13诱导的AHR和黏液产生。这些结果证明了IL-13对上皮细胞的直接作用在引发哮喘两个主要特征方面的重要性。
