Regulation of IL-1β–induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 46; pp. 18490 - 18495
• Main Authors: Scholz, Carsten C., Cavadas, Miguel A. S., Tambuwala, Murtaza M., Hams, Emily, Rodríguez, Javier, von Kriegsheim, Alex, Cotter, Philip, Bruning, Ulrike, Fallon, Padraic G., Cheong, Alex, Cummins, Eoin P., Taylor, Cormac T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.11.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Series: From the Cover
• Subjects: Analysis of Variance; animal models; Antiinflammatories; B lymphocytes; Biological Sciences; Blotting, Western; Enzymes; gene expression; Gene expression regulation; Gene Expression Regulation - physiology; HeLa Cells; Humans; Hydroxylation; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Immunoprecipitation; Inflammation; Inflammation - metabolism; Inflammation - physiopathology; interleukin-1beta; Interleukin-1beta - metabolism; Luciferases; Mass Spectrometry; Mixed Function Oxygenases - metabolism; NF-kappa B - metabolism; Oxygen; Plasmids; procollagen-proline dioxygenase; Prolyl Hydroxylases - metabolism; Protein isoforms; signal transduction; Signal Transduction - physiology; tissues; transcription (genetics); transcription factor NF-kappa B; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - metabolism; tumor necrosis factors; inflammatory disease; UBC13; oxygen; OTUB1
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1309718110

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.