Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study
Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study
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DOI：
10.1111/j.1365-2222.2008.03109.x
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发表时间：
2009-01-01
影响因子：
6.1
通讯作者：
Inman, M. D.
中科院分区：
文献类型：
--
作者：
Hirota, J. A.;Ask, K.;Inman, M. D.
哮喘是一种以可变和可逆的气道阻塞为特征的疾病，并且与气道炎症、气道重塑（包括杯状细胞增生、胶原沉积增加和平滑肌质量增加）和气道反应性增加相关。据信，气道炎症在气道重塑的发展中起关键作用，其中IL-13和TGF-β 1途径与疾病进展密切相关。哮喘的小鼠模型能够重现哮喘的一些组分，并且已经用于观察IL-13和TGF-β 1途径，其分别使用STAT 6和SMAD 2信号传导分子。我们利用BALB/c和C57 Bl/6，以探索观察到的这些小鼠品系之间对过敏原的反应差异将涉及IL-6的根本差异的假设。13和TGF-β 1反应。进行以下结果测量：气道生理学、支气管肺泡灌洗细胞计数/细胞因子分析、组织学、免疫印迹和基因表达测定。我们在BALB/c小鼠中证明了IL-13依赖性STAT 6磷酸化，核定位于炎症细胞中，这与气道重塑和气道功能障碍发展的指数相关。在BALB/c小鼠中，SMAD 2的磷酸化相对于STAT 6活化延迟，并且还涉及IL-13依赖性机制。相反，尽管变应原诱导的IL-4、IL-13和嗜酸性粒细胞增加，但C57 B1/6显示磷酸化STAT 6的减少和独特的模式，没有SMAD 2磷酸化改变，并且不能发展重塑或气道功能改变的指数。β 1进一步支持这些分子在哮喘动物模型的病理学和功能障碍中的中心作用。IL-13和TGF-β 1下游信号通路的激活与疾病进展的相关性可能比单独的气道炎症升高更大。
Asthma is a disease characterized by variable and reversible airway obstruction and is associated with airway inflammation, airway remodelling (including goblet cell hyperplasia, increased collagen deposition and increased smooth muscle mass) and increased airway responsiveness. It is believed that airway inflammation plays a critical role in the development of airway remodelling, with IL-13 and TGF-beta 1 pathways being strongly associated with the disease progression. Mouse models of asthma are capable of recapitulating some components of asthma and have been used to look at both IL-13 and TGF-beta 1 pathways, which use STAT6 and SMAD2 signalling molecules, respectively.Using brief and chronic models of allergen exposure, we utilized BALB/c and C57Bl/6 to explore the hypothesis that observed differences in responses to allergen between these mouse strains will involve fundamental differences in IL-13 and TGF-beta 1 responses.The following outcome measurements were performed: airway physiology, bronchoalveolar lavage cell counts/cytokine analysis, histology, immunoblots and gene expression assays.We demonstrate in BALB/c mice an IL-13-dependent phosphorylation of STAT6, nuclear localized in inflammatory cells, which is associated with indices of airway remodelling and development of airway dysfunction. In BALB/c mice, phosphorylation of SMAD2 is delayed relative to STAT6 activation and also involves an IL-13-dependent mechanism. In contrast, despite an allergen-induced increase in IL-4, IL-13 and eosinophils, C57Bl/6 demonstrates a reduced and distinct pattern of phosphorylated STAT6, no SMAD2 phosphorylation changes and fail to develop indices of remodelling or changes in airway function.The activation of signalling pathways and nuclear translocation of signalling molecules downstream of IL-13 and TGF-beta 1 further support the central role of these molecules in the pathology and dysfunction in animal models of asthma. Activation of signalling pathways downstream from IL-13 and TGF-beta 1 may be more relevant in disease progression than elevations in airway inflammation alone.