Abstract
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.
Highlights
The intestine harbor huge numbers of immunocompetent cells to manage elaborate interactions with microbes, for tolerance to luminal microbiota, as well as protection against invading pathogens
When HeLa cells were treated with 10 μM CG-598, hypoxiainducible factor (HIF)-1a but not HIF-2a was stabilized similar to AKB-4924, CoCl2 enhanced both (Figure 1B and Supplementary Figure 1B)
Intestinal epithelial cells were not affected by CG-598 at steady state, and CG-598 induced intestinal trefoil factor (ITF) and CD73 expression under cellular stress by 3% dextran sulfate sodium (DSS) treatment (Figure 1C and Supplementary Figure 1C)
Summary
The intestine harbor huge numbers of immunocompetent cells to manage elaborate interactions with microbes, for tolerance to luminal microbiota, as well as protection against invading pathogens. When genetic susceptibility is combined with environmental factors, chronic uncontrolled inflammatory diseases such as inflammatory bowel disease (IBD) are initiated [1]. Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are clinically chronic relapsing. The Therapeutic Effect of CG-598 diseases associated with dysregulated microbial composition (dysbiosis) and defective immune regulation. To investigate IBD therapeutics, various approaches have mainly focused on control of inflammation using anti-inflammatory drugs or immunosuppressants because inflammation is the obvious and most important final disease outcome regardless of the complicated pathogenesis of IBD [2]. Biologics for blockade of tumor necrosis factor (TNF) or integrin, key mediators of pathogenic inflammation have been increasingly applied. Clinical therapies as blockades of cytokine signaling via inhibition of intracellular Janus kinases (JAKs) such as tofacitinib were developed. Novel fundamental modulators from an understanding of underlying pathology should be investigated
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