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Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation

 Young-In Kim  ;  Eun-Je Yi  ;  Young-Dae Kim  ;  A Reum Lee  ;  Jiwoung Chung  ;  Hae Chan Ha  ;  Joong Myung Cho  ;  Seong-Ryeol Kim  ;  Hyun-Jeong Ko  ;  Jae-Hee Cheon  ;  Yong Rae Hong  ;  Sun-Young Chang 
 FRONTIERS IN IMMUNOLOGY, Vol.11 : 609689, 2021-01 
Journal Title
Issue Date
Animals ; Caco-2 Cells ; Cell Line, Tumor ; Colitis / drug therapy ; Colitis / immunology ; Colitis / metabolism ; Cytokines / immunology ; Cytokines / metabolism ; Disease Models, Animal ; Female ; HCT116 Cells ; HeLa Cells ; Humans ; Hypoxia / drug therapy ; Hypoxia / immunology ; Hypoxia / metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit / immunology* ; Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* ; Inflammation / immunology* ; Inflammation / metabolism* ; Inflammatory Bowel Diseases / drug therapy ; Inflammatory Bowel Diseases / immunology ; Inflammatory Bowel Diseases / metabolism ; Intestinal Mucosa / drug effects ; Intestinal Mucosa / immunology* ; Intestinal Mucosa / metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Prolyl-Hydroxylase Inhibitors / pharmacology ; Trefoil Factor-3 / immunology ; Trefoil Factor-3 / metabolism
gut barrier ; hypoxia-inducible factor ; immune regulation ; inflammatory bowel disease ; prolyl hydroxylase inhibitor
Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4+ T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
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