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Regulation of IL-1?-induced NF-?B 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 ?B (NF-?B), 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-1?, a major proinflammatory cytokine that regulates NF-?B, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1?-induced NF-?B at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1?-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-1? signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1?-dependent inflammatory signaling.

SUBMITTER: Scholz CC

PROVIDER: S-EPMC3832034 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

Scholz Carsten C CC Cavadas Miguel A S MA Tambuwala Murtaza M MM Hams Emily E Rodríguez Javier J von Kriegsheim Alex A Cotter Philip P Bruning Ulrike U Fallon Padraic G PG Cheong Alex A Cummins Eoin P EP Taylor Cormac T CT

Proceedings of the National Academy of Sciences of the United States of America 20131021 46

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 ...[more]

PMID: 24145445

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Regulation of IL-1?-induced NF-?B by hydroxylases links key hypoxic and inflammatory signaling pathways.

Publications

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

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