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

Abstract

NFκB 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 NFκB-induced inflammation has more recently been appreciated. Identification of the co-regulation of NFκB and hypoxia inducible factor (HIF) pathways by 2-oxo-glutarate-dependent hydroxylase family members has highlighted an intimate relationship between NFκB inflammatory signalling and HIF-mediated hypoxic signalling pathways. Adding another layer of complexity to our understanding of the role of NFκB inflammatory signalling by hypoxia is the recent recognition of the contribution of basal NFκB activity to HIF-1α transcription. This observation implicates an important and previously unappreciated role for NFκB in inflammatory disease where HIF-1α is activated. The present review will discuss recent literature pertaining to the regulation of NFκB 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.