期刊
INFECTION AND IMMUNITY
卷 82, 期 9, 页码 3531-3541出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00674-13
关键词
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资金
- Science Foundation of Ireland [SSPC2 12/RC/2275, 13-TIDA-B2625, 07/IN.1/B948, 12/TIDA/B2411, 12/TIDA/B2405, 09/RFP/BMT 2350]
- Department of Agriculture, Fisheries and Food [DAFF11/F/009 MabS, FIRM/RSF/CoFoRD, FIRM 08/RDC/629]
- Environmental Protection Agency [EPA 2008-PhD/S-2]
- Irish Research Council for Science, Engineering and Technology [PD/2011/2414, RS/2010/2413]
- European Commission [OCEAN2012 287589, FP7-KBBE-2012-6 CP-TP 311975, FP7-KBBE-2012-6 CP-TP-312184, 256596, FP7-PEOPLE-2013-ITN 607786]
- Marine Institute (Beaufort award) [C2CRA 2007/082]
- Teagasc (Walsh Fellowship)
- Health Research Board [HRA/2009/146]
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 1 alpha (HIF-1 alpha) protein, an emerging master regulator in response to infection and inflammation. HIF-1 alpha 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-1 alpha 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-1 alpha, 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.
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