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

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.