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-oxoglutarate-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 prolyl-hydroxylase inhibitors in inflammatory disease. NFκ κBThe transcription factor NFκB has been investigated for its diverse range of functions in innate immunity, stress responses, cell survival and development. It is also the master regulator of the inflammatory response [1]. An in-depth review of the NFκB pathway is beyond the scope of the present article, and there are several excellent reviews dedicated specifically to this topic [2,3].Briefly, the NFκB family comprises five members: p65, Rel B, cRel, p50 and p52. These proteins share a highly conserved Rel homology domain. In order to bind DNA and modulate gene expression, family members form homodimers or heterodimerswith the exception of Rel B, which will only form heterodimers with p50 or p52 [4]. The most commonly encountered dimer complex is the p50-p65 dimer [5]. There are two primary activation pathways for NFκB: the canonical pathway, which is predominantly dependent on inhibitor of κB kinase (IKK) beta, and the IKKα-dependent noncanonical pathway [6].Under resting conditions, NFκB is bound to its co-repressor molecule IκB in the cytosol, with which it interacts through multiple ankyrin repeats. A nuclear localisation sequence of the p65 protein is masked and it remains predominantly sequestered in the cytosolic compartment. Upon stimulation IκBα is phosphorylated at serine 32 and serine 36, targeted for ubiquitination and thereafter degraded proteolytically by the 26S proteosome [7]. A nuclear localisation sequence of NFκB is then revealed, and this is free to translocate and accumulate in the nucleus where it can become transcriptionally active by binding to specific κB sites within the promoter regions of its target genes [8]. The stimulus for IκBα to release the inhibition of NFκB has been identified as phosphorylation by the 700 kDa IKKα/β/γ protein complex.Genes induced by NFκB include those responsible for encodi...

The role of hypoxia-inducible factor 1 in atherosclerosis: Figure 1

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Nitric Oxide, Cytochrome C Oxidase, and the Cellular Response to Hypoxia

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Attenuated expression and function of the RECK tumor suppressor under hypoxic conditions is mediated by the MAPK signaling pathways

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