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dc.contributor.authorLegendre, C.
dc.contributor.authorReen, F.
dc.contributor.authorWoods, D.
dc.contributor.authorMooij, M.
dc.contributor.authorAdams, C.
dc.contributor.authorO'Gara, Fergal
dc.identifier.citationLegendre, C. and Reen, F. and Woods, D. and Mooij, M. and Adams, C. and O'Gara, F. 2014. Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response. Infection and Immunity. 82 (9): pp. 3531-3541.

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.

dc.publisherAmerican Society for Microbiology
dc.titleBile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response
dc.typeJournal Article
dcterms.source.titleInfection and Immunity
curtin.departmentSchool of Biomedical Sciences
curtin.accessStatusOpen access via publisher

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