title: Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways.
abstract: Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1β signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1β-dependent inflammatory signaling.
authors.affiliation: Systems Biology Ireland, School of Medicine and Medical Science, and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Carsten C
authors.initials: CC
authors.lastname: Scholz
authors.forename: Miguel A S
authors.initials: MA
authors.lastname: Cavadas
authors.forename: Murtaza M
authors.initials: MM
authors.lastname: Tambuwala
authors.forename: Emily
authors.initials: E
authors.lastname: Hams
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.forename: Philip
authors.initials: P
authors.lastname: Cotter
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bruning
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Alex
authors.initials: A
authors.lastname: Cheong
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D008156:Luciferases; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D006899:Mixed Function Oxygenases; D008156:Luciferases; D064828:Prolyl Hydroxylases
keywords: OTUB1; UBC13; inflammatory disease; oxygen