title: Bile acids repress hypoxia-inducible factor 1 signaling and modulate the airway immune response.
abstract: 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.
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Legendre
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: F Jerry
authors.initials: FJ
authors.lastname: Reen
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: David F
authors.initials: DF
authors.lastname: Woods
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Marlies J
authors.initials: MJ
authors.lastname: Mooij
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Adams
authors.affiliation: BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland Curtin University, School of Biomedical Sciences, Perth, WA, Australia f.ogara@ucc.ie.
authors.forename: Fergal
authors.initials: F
authors.lastname: O'Gara
mesh_terms: D001647:Bile Acids and Salts / Q000276:immunology* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D001647:Bile Acids and Salts; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D016209:Interleukin-8; D064828:Prolyl Hydroxylases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease