Peer-Reviewed Journal Details
Mandatory Fields
Legendre, C.,Reen, F. J.,Woods, D. F.,Mooij, M. J.,Adams, C.,O'Gara, F.
Infection and Immunity
Bile acids repress hypoxia-inducible factor 1 signaling and modulate the airway immune response
Optional Fields
Bile Acids and Salts/*immunology/*pharmacology Cell Line Cell Line, Tumor Epithelial Cells/drug effects/*immunology/metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism Inflammation/immunology/metabolism Interleukin-6/immunology/metabolism Interleukin-8/immunology/metabolism Prolyl Hydroxylases/immunology/metabolism Proteasome Endopeptidase Complex/immunology/metabolism Respiratory System/*drug effects/*immunology/metabolism Signal Transduction/*drug effects/immunology
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 1alpha (HIF-1alpha) protein, an emerging master regulator in response to infection and inflammation. HIF-1alpha 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-1alpha 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-1alpha, 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.
1098-5522 (Electronic) 00
Grant Details