Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation

Abstract

Decreased oxygen availability (hypoxia) is a hallmark feature of the microenvironment in a number of chronic inflammatory conditions including arthritis and inflammatory bowel disease (IBD). Recent advances in our understanding of oxygen-dependent cell signalling have uncovered several mechanisms by which hypoxia impacts upon the development of inflammation through the coordinated expression of adaptive, inflammatory and apoptotic genes. Two central transcription factors involved in the regulation of this response are hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-kappaB) which display different degrees of sensitivity to activation during hypoxia. Furthermore, HIF and NF-kappaB demonstrate an intimate interdependence at several mechanistic levels. Recent studies indicate that these pathways may represent important new therapeutic targets in diseases characterized by hypoxic inflammation.

Figure 1. Model of regulation of the HIF pathway during hypoxic inflammation

During chronic inflammation, decreased tissue perfusion and increased energy demand causes hypoxia. This leads to inhibition of hydroxylases (PHD/FIH) and subsequent stabilization and transactivation of HIF. Simultaneous activation of the NF-κB pathway leads to transcriptional up-regulation of HIF mRNA expression which facilitates the activation of HIF signalling.

Figure 2. Model of regulation of the NF-κB pathway in hypoxic inflammation

During chronic inflammation, elevated cytokine levels promote inflammation through activation of the canonical (IKK complex-dependent) NF-κB pathway. Simultaneous hypoxia facilitates this response by decreasing hydroxylase activity which serves to de-repress NF-κB signalling.

Figure 3. Model of crosstalk between the HIF and NF-κB pathways in hypoxic inflammation

In chronic inflammatory disease, tissue hypoxia leads to decreased hydroxylase activity with the subsequent activation of HIF-dependent adaptive gene expression (1). Simultaneously, signalling in response to inflammatory ligands leads to NF-κB activity and subsequent inflammatory and anti-apoptotic gene expression (2). An extensive level of cross-talk between the two pathways also exists including NF-κB-dependent up-regulation of HIF-1α mRNA expression (3), HIF-dependent regulation of NF-κB activity (4) and regulation of NF-κB signalling by HIF-hydroxylases (5).