Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response
MetadataShow full item record
Gastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1α (HIF-1α) protein, an emerging master regulator in response to infection and inflammation. HIF-1α repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1α repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1α, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation.
Showing items related by title, author, creator and subject.
Reen, F.; Flynn, S.; Woods, D.; Dunphy, N.; Chróinín, M.; Mullane, D.; Stick, S.; Adams, C.; O'Gara, Fergal (2016)Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid ...
Reen, F.; Flynn, S.; Woods, D.; Chroinin, M.; Mullane, D.; Stick, S.; Adams, C.; O'Gara, Fergal (2015)Chronic respiratory infections associated with lung disease are a major cause of global morbidity and mortality. However, despite concerted global research efforts current treatment strategies remain extremely limited, ...
Aspirated bile: a major host trigger modulating respiratory pathogen colonisation in cystic fibrosis patientsReen, F.; Woods, D.; Mooij, M.; Chroinin, M.; Mullane, D.; Zhou, L.; Quille, J.; Fitzpatrick, D.; Glennon, J.; McGlacken, G.; Adams, C.; O'Gara, Fergal (2014)Chronic respiratory infections are a leading global cause of morbidity and mortality. However, the molecular triggers that cause respiratory pathogens to adopt persistent and often untreatable lifestyles during infection ...