ABSTRACT
Inflammation of human bronchial epithelia (HBE) activates the endoplasmic reticulum (ER) stress transducer inositol-requiring enzyme 1 (IRE1)α, resulting in IRE1α-mediated cytokine production. Previous studies demonstrated ubiquitous expression of IRE1α and gut-restricted expression of IRE1ß. We found that IRE1ß is also expressed in HBE, is absent in human alveolar cells, and is upregulated in cystic fibrosis and asthmatic HBE. Studies with Ire1ß(-/-) mice and Calu-3 airway epithelia exhibiting IRE1ß knockdown or overexpression revealed that IRE1ß is expressed in airway mucous cells, is functionally required for airway mucin production, and this function is specific for IRE1ß vs. IRE1α. IRE1ß-dependent mucin production is mediated, at least in part, by activation of the transcription factor X-box binding protein-1 (XBP-1) and the resulting XBP-1-dependent transcription of anterior gradient homolog 2, a gene implicated in airway and intestinal epithelial mucin production. These novel findings suggest that IRE1ß is a potential mucous cell-specific therapeutic target for airway diseases characterized by mucin overproduction.
