期刊
FRONTIERS IN IMMUNOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2020.609689
关键词
inflammatory bowel disease; gut barrier; hypoxia-inducible factor; prolyl hydroxylase inhibitor; immune regulation
类别
资金
- Ajou University Research Fund (2019), Republic of Korea
- National Research Foundation of Korea (NRF) - Ministry of Science, ICT and future Planning [NRF-2019R1I1A1A01057559, NRF-2020R1A2B5B01001690]
The novel drug CG-598 showed significant anti-inflammatory effects in an experimental murine colitis model, enhancing barrier function, reducing inflammatory lesions, and decreasing the expression of pro-inflammatory cytokines.
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-1 alpha 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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