{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T02:57:29Z","timestamp":1776567449392,"version":"3.51.2"},"reference-count":32,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"H2020","award":["847786"],"award-info":[{"award-number":["847786"]}]},{"name":"Era-Net JPIAMR","award":["50-52900-98-201"],"award-info":[{"award-number":["50-52900-98-201"]}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["2019\/02224-0"],"award-info":[{"award-number":["2019\/02224-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMW","doi-asserted-by":"publisher","award":["40-00812-98-14016"],"award-info":[{"award-number":["40-00812-98-14016"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Seventh Framework","award":["602525"],"award-info":[{"award-number":["602525"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The respiratory epithelium provides a first line of defense against pathogens. Hypoxia-inducible factor (HIF)1\u03b1 is a transcription factor which is stabilized in hypoxic conditions through the inhibition of prolyl-hydroxylase (PHD)2, the enzyme that marks HIF1\u03b1 for degradation. Here, we studied the impact of HIF1\u03b1 stabilization on the response of primary human bronchial epithelial (HBE) cells to the bacterial component, flagellin. The treatment of flagellin-stimulated HBE cells with the PHD2 inhibitor IOX2 resulted in strongly increased HIF1\u03b1 expression. IOX2 enhanced the flagellin-induced expression of the genes encoding the enzymes involved in glycolysis, which was associated with the intracellular accumulation of pyruvate. An untargeted pathway analysis of RNA sequencing data demonstrated the strong inhibitory effects of IOX2 toward key innate immune pathways related to cytokine and mitogen-activated kinase signaling cascades in flagellin-stimulated HBE cells. Likewise, the cell\u2013cell junction organization pathway was amongst the top pathways downregulated by IOX2 in flagellin-stimulated HBE cells, which included the genes encoding claudins and cadherins. This IOX2 effect was corroborated by an impaired barrier function, as measured by dextran permeability. These results provide a first insight into the effects associated with HIF1\u03b1 stabilization in the respiratory epithelium, suggesting that HIF1\u03b1 impacts properties that are key to maintaining homeostasis upon stimulation with a relevant bacterial agonist.<\/jats:p>","DOI":"10.3390\/cells11030391","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:44:33Z","timestamp":1643143473000},"page":"391","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIF-1\u03b1 Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Function"],"prefix":"10.3390","volume":"11","author":[{"given":"Ivan","family":"Ramirez-Moral","sequence":"first","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca L.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Division of Infectious Diseases, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo 04023-062, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe M.","family":"Butler","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4916-2866","authenticated-orcid":false,"given":"Michel","family":"van Weeghel","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-1368","authenticated-orcid":false,"given":"Natasja A.","family":"Otto","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex F.","family":"de Vos","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menno D.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9961-0842","authenticated-orcid":false,"given":"Riekelt H.","family":"Houtkooper","sequence":"additional","affiliation":[{"name":"Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"van der Poll","sequence":"additional","affiliation":[{"name":"Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Division of Infectious Diseases, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nri.2016.117","article-title":"Early local immune defences in the respiratory tract","volume":"17","author":"Iwasaki","year":"2017","journal-title":"Nat. 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