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

Abstract

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.

Figure 1

Hypoxia activates NFκB signalling via inhibitor of κB kinase. Under conditions of hypoxia, the hydroxylase-mediated repression of inhibitor of κB kinase (IKK) beta is suppressed – leading to enhanced IKKβ activity, enhanced IκBα phosphorylation and degradation as well as increased p65 NFκB activity. Factor-inhibiting hypoxia inducible factor inhibition by hypoxia or pharmacological inhibition reduces IκBα asparaginyl hydroxylation but does not appear to affect IκBα degradation. COX-2, cyclooxygenase 2; ICAM-1, intracellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; RANTES, regulated upon activation normal T-cell expressed and secreted; PHD-1, prolyl hydroxylase 1; VCAM-1, vascular cell adhesion molecule 1.

Figure 2

NFκB and hypoxia inducible factor 1 alpha cross-talk. Hypoxia acts as a stimulus for the activation of the inhibitor of κB kinase (IKK) complex as shown in Figure 1. Basal IKKβ-dependent NFκB activity is required for transcriptionally active dimer complexes to translocate to the nucleus and bind to a region -197/188 base pairs upstream of the hypoxia inducible factor (HIF)-1α promoter. This results in an increase in HIF-1α mRNA and protein levels. Several NFκB proteins have been detected at the HIF-1α promoter region by chromatin immunoprecipitation. Increased levels of HIF-1α are observed in chronically inflamed tissue such as the rheumatoid arthritis (RA) synovium and in the dermal glands of psoriatic skin. FIH, factor-inhibiting hypoxia inducible factor.