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Prolyl Hydroxylase 1 (PHD1) and Factor Inhibiting HIF (FIH) regulate IL-1β-induced NF-{kappa}B activity linking key hypoxic and inflammatory signaling pathways

Scholz, Carsten C, Kriegsheim, Alexander von, Tambuwala, Murtaza M, Hams, Emily, Cheong, Alex, Bruning, Ulrike, Fallon, Padraic G, Cummins, Eoin P and Taylor, Cormac T (2013) Prolyl Hydroxylase 1 (PHD1) and Factor Inhibiting HIF (FIH) regulate IL-1β-induced NF-{kappa}B activity linking key hypoxic and inflammatory signaling pathways. The FASEB Journal., 717.9 . pp. 15-16. [Journal article]

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URL: http://www.fasebj.org/cgi/content/meeting_abstract/27/1_MeetingAbstracts/717.9?sid=57c5b4bf-a419-4bb0-9bbf-2fffdb85e6f0

Abstract

Low oxygen concentration (hypoxia) is a feature of chronically inflamed tissues. Hydroxylases are oxygen-sensing enzymes, which control the transcriptional response to hypoxia and influence the course of inflammation through the regulation of HIF-and NF-{kappa}B-dependent pathways. Four different oxygen-sensing hydroxylases are known: Prolyl Hydroxylase 1, 2 and 3 (PHD1, 2, 3) and Factor Inhibiting HIF (FIH). Pharmacologic hydroxylase inhibition reduces inflammation in animal models of colitis, reperfusion injury and sepsis, however, the underlying mechanisms remain unclear. IL-1β is a major pro-inflammatory cytokine that activates NF-{kappa}B-dependent transcriptional pathways and is associated with numerous inflammatory pathologies. We investigated a role for hydroxylases in regulating IL-1β-dependent inflammatory signaling. We show that hydroxylase inhibition reduces IL-1β-induced NF-{kappa}B activity in a manner, which is dependent upon the combinatorial inhibition of PHD1 and FIH and results in repression of NF-{kappa}B-dependent genes. Hydroxylase inhibition reduced IL-1β-induced signaling upstream of JNK, p38 and IKK. Thus, combinatorial inhibition of PHD1 and FIH represents a new approach to the inhibition of inflammatory signaling pathways activated by IL-1β, which may be of benefit in inflammatory disorders.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmacy & Pharmaceutical Sciences
ID Code:29218
Deposited By: Dr Murtaza Tambuwala
Deposited On:11 Apr 2014 08:34
Last Modified:11 Apr 2014 08:34

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