Hypoxia. Regulation of NFkappaB signalling during inflammation: the role of hydroxylases.

NFkappaB is a master regulator of innate immunity and inflammatory signalling. Microenvironmental hypoxia has long been identified as being coincident with chronic inflammation. The contribution of microenvironmental hypoxia to NFkappaB-induced inflammation has more recently been appreciated. Identification of the co-regulation of NFkappaB and hypoxia inducible factor (HIF) pathways by 2-oxo-glutarate-dependent hydroxylase family members has highlighted an intimate relationship between NFkappaB inflammatory signalling and HIF-mediated hypoxic signalling pathways. Adding another layer of complexity to our understanding of the role of NFkappaB inflammatory signalling by hypoxia is the recent recognition of the contribution of basal NFkappaB activity to HIF-1alpha transcription. This observation implicates an important and previously unappreciated role for NFkappaB in inflammatory disease where HIF-1alpha is activated. The present review will discuss recent literature pertaining to the regulation of NFkappaB inflammatory signalling by hypoxia and some of the inflammatory diseases where this may play an important role. Furthermore, we will discuss the potential for prolylhydroxylase inhibitors in inflammatory disease.