RESUMO
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.
Assuntos
Asma/imunologia , Fibrose Cística/imunologia , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Mucosa Respiratória/imunologia , Animais , Asma/genética , Linhagem Celular , Fibrose Cística/genética , Proteínas de Ligação a DNA/metabolismo , Endorribonucleases/genética , Endorribonucleases/imunologia , Endorribonucleases/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Mucinas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/metabolismo , Transgenes/genética , Regulação para Cima , Proteína 1 de Ligação a X-BoxRESUMO
Chronic airway inflammation characterizes several airway diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The altered airway milieu that results from the pathogenic processes in these disorders affects the airway epithelia, leading to an up-regulation of their innate defense. In human airway epithelia, luminal inflammatory stimuli induce an adaptation characterized by an expansion of the endoplasmic reticulum (ER) and its Ca(2+) stores. This epithelial adaption mediates Ca(2+)-dependent "hyperinflammatory" responses, and recent studies have shown that activation of the unfolded protein response (UPR) by ER stress is involved in the process. The UPR is also known to be activated by cigarette smoke, the primary trigger for development of COPD. These studies illustrate the functional role of UPR pathways during airway inflammation and suggest that targeting the UPR may be a therapeutic strategy for obstructive airway diseases. This article reviews the link between airway epithelial inflammation and activation of the UPR, and discusses how UPR activation might be relevant for CF and COPD airways disease.