Hydroxylase-dependent regulation of the NF-κB pathway

Abstract

Hypoxia is associated with a diverse range of physiological and pathophysiological processes, including development, wound healing, inflammation, vascular disease and cancer. The requirement that eukaryotic cells have for molecular oxygen as the terminal electron acceptor for the electron transport chain means that the maintenance of oxygen delivery is key for bioenergetic homeostasis. Metazoans have evolved an effective way to adapt to hypoxic stress at the molecular level through a transcription factor termed the hypoxia inducible factor. A family of oxygen-sensing hydroxylases utilizes molecular oxygen as a co-substrate for the hydroxylation of hypoxia inducible factor α subunits, thereby reducing its expression and transcriptional activity when oxygen is available. Recent studies have indicated that other hypoxia-responsive transcriptional pathways may also be hydroxylasedependent. In this review, we will discuss the role of hydroxylases in the regulation of NF-κ B, a key regulator of immunity and inflammation. Developing our understanding of the role of hydroxylases in hypoxic inflammation may identify novel therapeutic approaches in chronic inflammatory disease.

Regulation of IL-1β–induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways

“…The same hydroxylases that confer hypoxic sensitivity upon HIF have been reported to be responsible for the hypoxic sensitivity of NF-κB (9). Whereas PHDs have been implicated in the regulation of NF-κB, the functional site(s) of proline hydroxylation in the pathway has yet to be identified (9)(10)(11). Conversely, FIH-dependent asparagine hydroxylation sites on a number of key proteins in the NF-κB pathway have been identified; however, the functional impact of this remains unclear (12,13).…”

“…The same hydroxylases that confer hypoxic sensitivity upon HIF have been reported to be responsible for the hypoxic sensitivity of NF-κB (9). Whereas PHDs have been implicated in the regulation of NF-κB, the functional site(s) of proline hydroxylation in the pathway has yet to be identified (9)(10)(11).…”

Regulation of immunity and inflammation by hypoxia in immunological niches

“…Finally, in intestinal epithelial cells (a key innate immune cell), HIF modulates ion transport, antimicrobial peptide production and barrier function 44,53,54 . Although the focus of the current Review is on the role of HIF in regulating immune cell function, it should be noted that other components of the HIF pathway (including both HIF hydroxylases and pVHL) can also regulate immune cell function through HIF-independent mechanisms 55–57 . Thus, substantial evidence now exists to support a role for HIF as a major regulator of innate and adaptive immune cell function, and HIF should therefore be considered as a central transcriptional regulator of immunity.…”

Cycling hypoxia: A key feature of the tumor microenvironment

“…In addition to HIF-1, two other transcription factors have also been reported to be activated by cycling hypoxia: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) in endothelial cells [43] and in cancer cells [41] as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in A459 lung carcinoma cells [39]. As for HIF-1, the activation of Nrf2 and NF-B by fluctuations in oxygenation levels was found to be mediated, at least in part, by an increased ROS production [44,45]. As a consequence of the activation of the above transcription factors, cycling hypoxia affects cell behavior through profound changes in gene expression.…”