X-Box-Binding Protein 1 and Innate Immune Responses of Human Cystic Fibrosis Alveolar Macrophages
X-Box-Binding Protein 1 and Innate Immune Responses of Human Cystic Fibrosis Alveolar Macrophages
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DOI：
10.1164/rccm.201504-0657oc
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发表时间：
2015-12-01
影响因子：
24.7
通讯作者：
Ribeiro, Carla M. P.
中科院分区：
文献类型：
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作者：
Lubamba, Bob A.;Jones, Lisa C.;Ribeiro, Carla M. P.
原理：肺泡巨噬细胞（AMs）在宿主防御吸入性细菌病原体中发挥关键作用，部分是通过分泌炎症介质。囊性纤维化（CF）气道表现出持续的、强烈的炎症反应，这可能与CF的病理生理有关。最近的研究发现，由肌醇需要酶1 α依赖信使RNA剪接（激活）x- box结合蛋白1 （xbp -1）介导的内质网应激反应与外周巨噬细胞的炎症有关。然而，xbp -1在CF AM功能中的作用尚不清楚。目的：评估慢性感染/炎症的人CF肺中am的炎症反应，并检测am介导的炎症是否需要xbp -1。方法：在非CF和CF am的原代培养中评估基础和lps诱导的炎症反应。使用8-甲酰基-7-羟基-4-甲基香豆素（4 μ 8C）（一种肌醇需要酶1a依赖性XBP-1的抑制剂）和稳定表达XBP-1 shRNA、XBP-1或显性阴性XBP-1的THP-1细胞，在AMs中测量XBP-1并评估其功能。测量结果和主要结果：CF am表现出基础和lps诱导的肿瘤坏死因子α和IL-6的过量产生，这些反应与xbp -1水平的增加相关联。在非CF和CF am中，lps诱导的细胞因子产生被4 μ 8C钝化。来自dTHP-1细胞的数据进一步证实了XBP-1在AM炎症反应中的作用，表明XBP-1 shRNA的表达降低了XBP-1水平和脂多糖诱导的炎症反应；lps诱导的炎症可通过XBP-1的表达上调，并被显性阴性的XBP-1抑制。结论：这些发现表明，am通过上调xbp -1s介导的细胞因子产生，促进CF气道的强烈炎症。
Rationale: Alveolar macrophages (AMs) play a key role in host defense to inhaled bacterial pathogens, in part by secreting inflammatory mediators. Cystic fibrosis (CF) airways exhibit a persistent, robust inflammatory response that may contribute to the pathophysiology of CF. Recent findings have linked endoplasmic reticulum stress responses mediated by inositol-requiring enzyme 1 alpha-dependent messenger RNA splicing (activation) of X-box-binding protein-1 (XBP-1s) to inflammation in peripheral macrophages. However, the role of XBP-1s in CF AM function is not known.Objectives: To evaluate inflammatory responses of AMs from chronically infected/inflamed human CF lungs and test whether XBP-1s is required for AM-mediated inflammation.Methods: Basal and LPS-induced inflammatory responses were evaluated in primary cultures of non-CF versus CF AMs. XBP-1s was measured and its function was evaluated in AMs using 8-formyl-7-hydroxy-4-methylcoumarin (4 mu 8C), an inhibitor of inositol-requiring enzyme 1a-dependent XBP-1s, and in THP-1 cells stably expressing XBP-1 shRNA, XBP-1s, or a dominant-negative XBP-1.Measurements and Main Results: CF AMs exhibited exaggerated basal and LPS-induced production of tumor necrosis factor-alpha and IL-6, and these responses were coupled to increased levels of XBP-1s. In non-CF and CF AMs, LPS-induced cytokine production was blunted by 4 mu 8C. A role for XBP-1s in AM inflammatory responses was further established by data from dTHP-1 cells indicating that expression of XBP-1 shRNA reduced XBP-1s levels and LPS-induced inflammatory responses; and LPS-induced inflammation was up-regulated by expression of XBP-1s and inhibited by dominant-negative XBP-1.Conclusions: These findings suggest that AMs contribute to the robust inflammation of CF airways via an up-regulation of XBP-1s-mediated cytokine production.