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Review
. 2015 Apr;35(4):859-69.
doi: 10.3892/ijmm.2015.2079. Epub 2015 Jan 27.

The role of hypoxia in inflammatory disease (review)

John Biddlestone  1 , Daniel Bandarra  1 , Sonia Rocha  1
Affiliations
Review

The role of hypoxia in inflammatory disease (review)

John Biddlestone et al. Int J Mol Med. 2015 Apr.

Abstract

Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation. These stimuli commonly occur together in vivo and there is significant crosstalk between the transcription factors that are classically understood to respond to either hypoxia or inflammation. This crosstalk can be used to modulate the overall response to environmental stress. Several common disease processes are characterised by aberrant transcriptional programs in response to environmental stress. In this review, we discuss the current understanding of the role of the hypoxia-responsive (hypoxia-inducible factor) and inflammatory (nuclear factor-κB) transcription factor families and their crosstalk in rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, with relevance for future therapies for the management of these conditions.

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Figures

Figure 1
Figure 1
(A) Schematic diagram of HIF proteins. Boxes represent different protein domains. The hydroxylation sites for HIF-1α and HIF-2α are noted above the schematic structure. (B) Schematic diagram of HIF pathway. In the presence of oxygen (normoxia), c bind to HIF-1α and catalyse the hydroxylation of proline residues. Once hydroxylated, HIF-1α binds rapidly to the vHL, which results in its polyubiquitination. This targets HIF-1α for proteasome-mediated degradation. In the presence of low oxygen (hypoxia), HIF-1α is stabilized and can translocate to the nucleus. HIF-1α dimerises with its partner HIF-1β and transactivates target genes containing hypoxia response elements (HREs). HIF, hypoxia-inducible factor; vHL, von Hippel Lindau; bHLH, basic helix-loop-helix; CTAD, C-terminal transactivation domain; LZIP, leucine zipper; NLS, nuclear localisation signal; ODD, oxygen-dependent domain; PAS, Per/ARNT/Sim domain.
Figure 2
Figure 2
(A) Schematic diagram of NF-κB subunits. p50 and p52 are not shown, and they are derived from p105 and p100, respectively. Boxes represent different protein domains. (B) NF-κB canonical pathway. The presence of a stimuli results in the activation of the IKK complex, which mediates the phosphorylation of IκB protein, which signals it for proteasomal degradation. This results in NF-κB dimer release and translocation into the nucleus. NF-κB, nuclear factor-κB; IKK, inhibitor of κB kinase; RHD, Rel homology domain; TAD, C-terminal transactivation domain; LZ, leucine zipper motif; NLS, nuclear localisation signal; ANK, ankyrin-repeat motifs; DD, death domain.
Figure 3
Figure 3
HIF and NF-κB crosstalk in RA. In RA, the synovial join is characterised by hypoxic and inflammatory regions (in blue and red, respectively). Hypoxia leads to the activation of HIF-1α, which is involved in several cellular processes (such as apoptosis, vasomotor control, energy metabolism and angiogenesis). Additionally, hypoxia leads to the activation of HIF-2α, which is involved in the activation of pro-inflammatory cytokines. In RA, inflammation leads to the activation of NF-κB, which activates a pro-inflammatory programme, including pro-inflammatory cytokines, chemokines, metalloproteases and metabolic proteins. While HIF-1α has been implicated in the repression of the NF-κB pathway (59), HIF-2α has been shown to increase inflammation (78). In RA, this crosstalk remains poorly understood. RA, rheumatoid arthritis; HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB.
Figure 4
Figure 4
HIF and NF-κB crosstalk in inflammatory bowel disease. In IBD, the intestinal mucosa is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and acts as a protective barrier by inhibiting apoptosis of epithelial cells, enhancing the barrier-protective genes, and by promoting the apoptosis in neutrophils. Inflammation leads to the activation of NF-κB, which is involved in the expression of inflammatory cytokines that can lead to inflammation and/or NF-κB activation. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; IBD, inflammatory bowel disease.
Figure 5
Figure 5
HIF and NF-κB crosstalk in CRC. In CRC, the intestinal lumen is characterised by hypoxic and inflammatory regions (in blue and red, respectively). HIF-1α is activated in hypoxia, and is involved in the modulation of tumour growth, apoptosis, and EMT. Inflammation leads to the activation of NF-κB, which is involved in the expression of pro-inflammatory cytokines, ROS production, and tumour survival. In CRC, there are some points of crosstalk between NF-κB and HIF, namely in the regulation of p53, APC, and cMyc. HIF, hypoxia-inducible factor; NF-κB, nuclear factor-κB; CRC, colorectal cancer; EMT, epithelial to mesenchymal transition; ROS, reactive oxygen species; APC, adenomatous polyposis coli.
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