X-Box-Binding Protein 1 and Innate Immune Responses of Human Cystic Fibrosis Alveolar Macrophages

American Journal of Respiratory and Critical Care Medicine
Bob A LubambaCarla M P Ribeiro

Abstract

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 1α-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. To evaluate inflammatory responses of AMs from chronically infected/inflamed human CF lungs and test whether XBP-1s is required for AM-mediated inflammation. 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 (4μ8C), an inhibitor of inositol-requiring enzyme 1α-dependent XBP-1s, and in THP-1 cells stably expressing XBP-1 shRNA, XBP-1s, or a dominant-negative XBP-1. CF AMs exhibited exaggerated basal and LPS-induced production of tumor necrosis factor-α and IL-6, and these responses were coupled to increased levels of XBP-1s. In ...Continue Reading

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Citations

Jan 12, 2017·International Journal of Molecular Sciences·Carla M P Ribeiro, Bob A Lubamba
May 13, 2017·Médecine sciences : M/S·Bob A Lubamba
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