S15 Aryl hydrocarbon receptor signaling protects mice from inflammatory bowel disease

Abstract

Background and aim: Excessive Th1-mediated immune response promotes pathogenic inflammation in the gut. Indeed, therapeutic interventions targeting Th1-type cytokines have already shown great promise for the treatment of patients with inflammatory bowel diseases (IBD). The aryl hydrocarbon receptor (AhR), a cytosolic transcription factor best known for mediating the dioxin-toxicity, has been recently reported to modulate Th cell responses. Aim: To evaluate if AhR-signalling controls pathogenic Th1 cell-mediated inflammation in the gut. Material and methods: 6-formylindolo[3,2-b]carbazole (FICZ), a highaffinity ligand of AhR, or the AhR antagonist, 2-metyl-2H-pyrazole-3carboxylic acid, were intraperitoneally administered to mice with acute 2,4,6trinitrobenzene-sulfonic acid (TNBS) or chronic dextrane-sodium-sulfate (DSS). Lamina propria mononuclear cells (LPMC) were analyzed for inflammatory and anti-inflammatory molecules by real-time-PCR and flow citometry. To evaluate whether the anti-inflammatory effect of AhR was mediated by IL22, mice were injected with a neutralizing IL-22 antibody 6 hours prior to being treated with FICZ. Th1-related cytokines were also analyzed in Crohn’s disease (CD) mucosal explants and LPMC either left untreated or treated with FICZ. Results: FICZ-treated mice were largely protected against TNBS and DSS colitis, and showed a marked down-regulation of pro-inflammatory molecules, such as IFN-gamma, TNF-alpha, IL-6, IL-12, and T-bet. This was associated with induction of IL-22, and no change in the fractions of IL-10 or Foxp3positive cells. Flow-cytometry analysis revealed that both T and non-T cells were major sources of IL-22 in FICZ-treated mice. Notably, neutralization of endogenous IL-22 with the blocking IL-22 antibody largely prevented the FICZ-mediated therapeutic effect in mice with TNBS-colitis. Abrogation of AhR-signaling reduced colonic IL-22 expression, thus leading to the development of a severe TNBS-colitis. Finally, we showed that FICZ markedly reduced Th1-related markers in CD mucosal explants and LPMC. Conclusions: Data show that AhR-driven signals inhibit pathogenic responses in the gut, and suggest that AhR-related compounds may be therapeutically useful in human IBD, such CD. # G. Inflammatory bowel diseases 1. Basic science