Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade.
OBJECTIVE
Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known.


METHODS
With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction.


RESULTS
In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor.


CONCLUSIONS
The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.
Shah
Yatrik M
YM
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ito
Shinji
S
Morimura
Keiichirou
K
Chen
Chi
C
Yim
Sun-Hee
SH
Haase
Volker H
VH
Gonzalez
Frank J
FJ
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011995:Recombination, Genetic; D015398:Signal Transduction; D013997:Time Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D019426:Integrases; D019746:Intramolecular Oxidoreductases; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C497397:Arnt protein, mouse; C497443:Hif1a protein, mouse; C045073:Cre recombinase; C076231:Mif protein, mouse; C494469:VHL protein, mouse