Prolyl Hydroxylase 1 (PHD1) and Factor Inhibiting HIF (FIH) regulate IL‐1β‐induced NF‐κB activity linking key hypoxic and inflammatory signaling pathways

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‐κB‐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‐κB‐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‐κB activity in a manner, which is dependent upon the combinatorial inhibition of PHD1 and FIH and results in repression of NF‐κB‐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.