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The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

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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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.
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f4-ijmm-35-04-0859: 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.

Mentions: The intestinal mucosa is exposed to steep hypoxic gradients (63) and is in a constant state of controlled inflammation, which is necessary to allow tolerance to otherwise harmless ingested dietary antigens (Fig. 4) (84). This fine balance is pathologically disturbed in inflammatory bowel disease (IBD); a relapsing-remitting progressive disorder of the gastrointestinal tract that comprises both Crohn’s and ulcerative colitis. The symptoms of IBD can range from mild to severe and include abdominal pain, intestinal bleeding, weight loss, fever and diarrhoea (85). The two IBD sub-types have different distribution patterns: ulcerative colitis is restricted to the colon, whereas Crohn’s colitis can affect any part of the GI tract. Both are thought to occur when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material and further cycles of inflammation and barrier dysfunction that underlie disease progression (86,87).


The role of hypoxia in inflammatory disease (review).

Biddlestone J, Bandarra D, Rocha S - Int. J. Mol. Med. (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356629&req=5

f4-ijmm-35-04-0859: 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.
Mentions: The intestinal mucosa is exposed to steep hypoxic gradients (63) and is in a constant state of controlled inflammation, which is necessary to allow tolerance to otherwise harmless ingested dietary antigens (Fig. 4) (84). This fine balance is pathologically disturbed in inflammatory bowel disease (IBD); a relapsing-remitting progressive disorder of the gastrointestinal tract that comprises both Crohn’s and ulcerative colitis. The symptoms of IBD can range from mild to severe and include abdominal pain, intestinal bleeding, weight loss, fever and diarrhoea (85). The two IBD sub-types have different distribution patterns: ulcerative colitis is restricted to the colon, whereas Crohn’s colitis can affect any part of the GI tract. Both are thought to occur when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material and further cycles of inflammation and barrier dysfunction that underlie disease progression (86,87).

Bottom Line: Mammals have developed evolutionarily conserved programs of transcriptional response to hypoxia and inflammation.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.

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.

Show MeSH
Related in: MedlinePlus