期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 192, 期 12, 页码 1449-1461出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201504-0657OC
关键词
cystic fibrosis; airway inflammation; alveolar macrophage; UPR; IRE1 alpha/XBP-1
资金
- National Heart, Lung, and Blood Institute [5 P01 HL 108808-02S1]
- National Institute of Diabetes and Digestive and Kidney Diseases [P30DK065988]
- Cystic Fibrosis Foundation [CFF R026]
- Wallonia-Brussels International
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.
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