title: Toll-like receptor activation and hypoxia use distinct signaling pathways to stabilize hypoxia-inducible factor 1α (HIF1A) and result in differential HIF1A-dependent gene expression.
abstract: HIF1A is a transcription factor that plays a central role for the adaptation to tissue hypoxia and for the inflammatory response of myeloid cells, including DCs. HIF1A is stabilized by hypoxia but also by TLR ligands under normoxic conditions. The underlying signaling events leading to the accumulation of HIF1A in the presence of oxygen are still poorly understood. Here, we show that in contrast to hypoxic stabilization of HIF1A, normoxic, TLR-mediated HIF1A accumulation in DCs follows a different pathway that predominantly requires MYD88-dependent NF-κB activity. The TLR-induced HIF1A controls a subset of proinflammatory genes that are insufficiently induced following hypoxia-mediated HIF1A induction. Thus, TLR activation and hypoxia stabilize HIF1A via distinct signaling pathways, resulting in differential HIF1A-dependent gene expression.
authors.affiliation: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. jonathan.jantsch@uk-erlangen.de
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
authors.forename: Melanie
authors.initials: M
authors.lastname: Wiese
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.forename: Kirstin
authors.initials: K
authors.lastname: Castiglione
authors.forename: Joachim
authors.initials: J
authors.lastname: Gläsner
authors.forename: Sophie
authors.initials: S
authors.lastname: Kolbe
authors.forename: David
authors.initials: D
authors.lastname: Mole
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Michael
authors.initials: M
authors.lastname: Hensel
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.forename: Markus
authors.initials: M
authors.lastname: Schnare
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; C497443:Hif1a protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse