Targeting Interleukin-23(p19) secretion from intestinal epithelial cells to improve intestinal barrier integrity in inflammatory bowel disease — ASN Events
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  2. Poster Session Three
  3. Targeting Interleukin-23(p19) secretion from intestinal epithelial cells to improve intestinal barrier integrity in inflammatory bowel disease

Targeting Interleukin-23(p19) secretion from intestinal epithelial cells to improve intestinal barrier integrity in inflammatory bowel disease (#402)

Ran Wang 1 , Rohan Lourie 1 2 , Hui Tong 1 , Rabina Giri 1 , Veronika Schreiber 1 , JakeJakob Begun 1 2 , Tim F Florin 1 2 , Michael A McGuckin 1 3 , Sumaira Z Hasnain 1 3
  1. Mater Research Institute - UQ, Woolloongabba, QLD, Australia
  2. Mater Adult Hospital, Mater Health Service, South Brisbane, QLD 4102, Australia
  3. Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia

Background Genome-wide association studies identified Il23r as an inflammatory bowel disease (IBD) associated gene. Anti-IL-23 antibodies are in use for Crohn’s disease and trials in ulcerative colitis are ongoing. It is known that IL-23, a dimer composed of IL-12p40 and IL-23p19, promotes and sustains proinflammatory TH17 response. Besides its effects on T cells, IL-23 recruits or activates macrophages, neutrophils and endothelial cells during mucosal inflammation. These functions identify IL-23 as a promising target for inflammatory diseases. Winnie mice share similarities with human ulcerative colitis, developing progressive intestinal inflammation derived from an epithelial defect and driven by a mixed but IL-23/TH17-dominated proinflammatory response. The aim of this study was to determine the effects and the mechanisms by which anti-IL-23 therapy suppresses colitis in Winnie mice.

Results Two weeks anti-IL-23(anti-p19) treatment significantly ameliorated established colitis in Winnie mice. Interestingly, the treatment did not dampen proinflammatory cytokine production from cultured mesenteric lymph nodes, suggesting that the efficacy of anti-IL-23 may be due to mechanisms other than suppressing cytokine-producing immune cells. We noted diminished colonic neutrophil infiltration, and downregulated chemokine mRNA expression in isolated colonic epithelial cells and restored colonic goblet cell mucin production. Here, we demonstrate in this study that stressed intestinal epithelial cells also produce IL-23p19. In Winnie mice which have increased intestinal cell endoplasmic reticulum stress, IL-23 expression is upregulated in epithelial cells compared to wildtype mice. This is the first demonstration of the epithelial source of IL-23p19 and that it may contribute to increased neutrophil recruitment in inflammation. Anti-IL-23 treatment was also associated with decreased intestinal endothelial cell activation as indicated by downregulation of E-selectin and Icam-1 expression in Winnie mice compared to control mice. 

Conclusion Neutralisation of IL-23p19 is likely to be efficacious in IBD due to its multiple mechanism of action on different cell types.

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