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Hypoxia-inducible factor-1 (HIF-1) activation in myeloid cells accelerates DSS-induced colitis progression in mice

Title
Hypoxia-inducible factor-1 (HIF-1) activation in myeloid cells accelerates DSS-induced colitis progression in mice
Authors
KIM, YOUNG EUNLEE, MINJIGu, HyejungKIM, JEONGWOOJeong, SeongjuYeo, SujinLEE, You JeongIM, SIN HYEOGSUNG, YOUNG CHULKim, Hak JaeWeissman, Irving L.AHN, G ONE
POSTECH Authors
LEE, You JeongIM, SIN HYEOGSUNG, YOUNG CHULAHN, G ONE
Date Issued
Jul-2018
Publisher
COMPANY OF BIOLOGISTS LTD
Abstract
nflammatory bowel disease (IBD) is a chronic inflammatory disease where the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated a role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways created by Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium binding protein as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice where HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared to wild-type (WT) mice. These parameters were restored to, if not better than the WT levels when we examined hMRP8 Hif-1α KO mice upon 5% DSS feeding. hMRP8 Hif-2α KO mice on the other hand exhibited similar degree of DSS-induced colitis to WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1α KO mice exhibited comparable levels of colorectal tumors to WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1 activation in myeloid cells critically regulates IBD progression.
URI
http://oasis.postech.ac.kr/handle/2014.oak/92301
DOI
10.1242/dmm.033241
ISSN
1754-8403
Article Type
Article
Citation
Disease Models & Mechanisms, vol. 11, no. 7, 2018-07
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 SUNG, YOUNG CHUL
Div of Integrative Biosci & Biotech
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