Hypoxia and inflammation are two sides of the same coin.

Hypoxia and inflammation share an interdependent relationship (1). Many recent publications implicate hypoxia-elicited inflammation, or inflammation during hypoxic conditions in the outcomes of a wide array of human diseases (2). On the one hand, inflammatory disease states are frequently characterized by tissue hypoxia, or stabilization of hypoxiadependent transcription factors, such as hypoxia-inducible factor (HIF) (3). For example, intestinal inflammation, such as occurs during inflammatory bowel disease, is characterized by the occurrence of severe hypoxia of the mucosal surface, and concomitant stabilization of HIF (4, 5). Stabilization of HIF1A during intestinal inflammation is caused by alterations in metabolic supply and demand ratios, particularly for oxygen, leading to “inflammatory hypoxia” (6). Similarly, lung inflammation, such as occurs during acute lung injury, is associated with metabolic alterations leading to the stabilization of HIF1A (7). On the other hand, disease conditions that are primarily caused by a lack of oxygen are characterized by secondary inflammatory changes. For example, ischemia and reperfusion injury is characterized by inflammatory responses that lead to subsequent organ dysfunction (8). The functional role of hypoxia-signaling and stabilization of HIFs during acute inflammatory or hypoxic disease states has been the focus of many recent studies. Surprisingly, many of these studies show that pharmacologic stabilization of HIF functions in an adaptive manner by increasing ischemia tolerance (9) and controlling excessive inflammation (10). Many of the studies have linked the anti-inflammatory effects of hypoxiasignaling to a transcriptional program that is under the control of HIF, where pharmacologic activators of HIFs provide tissue protection (11, 12). However, a recent study by Scholz et al. provides a different perspective on the mechanism of how hypoxiasignaling can function to dampen tissue inflammation (13). Scholz et al. provide compelling evidence that hydroxylases, which are inhibited by hypoxic conditions, modulate inflammation via key posttranslational modifications in the IL-1β pathway, with important implications for the use of hydroxylase inhibitors for the treatment of inflammatory disorders. Hydroxylases play a central role for the link between hypoxia and inflammation. Specifically, a set of four different hydroxylases— prolyl-hydroxylases (PHD)-1, PHD2, and PHD3, and the asparagine-hydroxylase factor-inhibiting HIF (FIH)—have been implicated in the posttranslational regulation of hypoxic and inflammatory signaling pathways (2). These four enzymes are known for their functional role in controlling the stability of the α-subunit of HIF. Both FIH and PHDs require oxygen as a cofactor for hydroxylation and if oxygen levels fall, FIH and PHDs are functionally inactive, thereby leading to the stabilization of HIF and subsequent activation of hypoxia-elicited genes. Therefore, hydroxylases, such as FIH and PHDs, play an important functional role as cellular oxygen sensors, by sensing the presence or Eltzschig HK, Carmeliet P. N Engl J Med 2011;364:656-665