A Critical Role of SHP-1 in Regulation of Type 2 Inflammation in the Lung
A Critical Role of SHP-1 in Regulation of Type 2 Inflammation in the Lung
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DOI：
10.1165/rcmb.2008-0225oc
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发表时间：
2009-05-01
影响因子：
6.4
通讯作者：
Zhu, Zhou
中科院分区：
文献类型：
--
作者：
Oh, Sun Young;Zheng, Tao;Zhu, Zhou
哮喘是一种慢性气道炎症性疾病。2型辅助性T（Th）细胞主导的肺部炎症是哮喘的标志。含Src同源2结构域的蛋白酪氨酸磷酸酶（SHP）-1在许多生长因子和细胞因子受体的信号传导途径中是负调节剂。然而，SHP-1在IL-4/IL-13信号通路中的直接作用尚未确定。在这项研究中，我们试图通过描述活蛾（mev）小鼠的肺部炎症来定义SHP-1在肺部的功能，并研究所涉及的分子机制。通过分析mev小鼠的肺组织学、生理学和细胞因子表达来确定炎症的性质，并使用基因缺失方法来鉴定相关的关键分子。在mev小鼠中，我们观察到肺中自发性Th 2样炎症反应，包括嗜酸性粒细胞增多、粘液化生、气道上皮肥大、肺纤维化以及气道阻力和气道高反应性增加。肺表型伴随Th 2细胞因子和趋化因子的上调。IL-13或信号转导子和转录激活子6（Th 2信号传导途径中的关键基因）的选择性缺失显著减少但不完全消除肺中的炎症。这些发现表明，SHP-1在调节IL-4/IL-13信号通路和维持肺内稳态中起关键作用。
Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell-dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. However, a direct role of SHP-1 in the IL-4/IL-13 signaling pathway has not been established. In this study, we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved. Pulmonary histology, physiology, and cytokine expression of mev mice were analyzed to define the nature of the inflammation, and the gene-deletion approach was used to identify critical molecules involved. In mev mice, we observed spontaneous Th2-like inflammatory responses in the lung, including eosinophilia, mucus metaplasia, airway epithelial hypertrophy, pulmonary fibrosis, and increased airway resistance and airway hyperresponsiveness. The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.