6-Formylindolo(3,2-b)carbazole Induced Aryl Hydrocarbon Receptor Activation Prevents Intestinal Barrier Dysfunction Through Regulation of Claudin-2 Expression
Overview
Molecular Biology
Pharmacology
Affiliations
6-Formylindolo(3,2-b)carbazole (FICZ), a high-affinity aryl hydrocarbon receptor (AhR) ligand, plays a protective role in inflammatory bowel disease (IBD) through activation of AhR. Interleukin-6 (IL-6) induced intestinal epithelial barrier dysfunction is involved in the pathological process of IBD. In this study, we investigated the protective effects of FICZ on IL-6 induced intestinal epithelial barrier injury. Our data show that AhR activation by FICZ ameliorated colonic inflammation, decreased IL-6 and claudin-2 expression, and maintained intestinal barrier function in a mouse model of dextran sulphate sodium (DSS)-induced colitis. In Caco-2 and T84 intestinal epithelial cells, FICZ also prevented the increase of intestinal epithelial permeability and claudin-2 expression induced by IL-6. Depletion of AhR expression by small interfering (si)RNA reversed FICZ induced decrease of claudin-2. Furthermore, IL-6 induced upregulation of claudin-2 was required for increased caudal-related homeobox 2 (CDX-2) and hepatocyte-nuclear factor (HNF)-1α. However, FICZ repressed the increase of CDX-2 and HNF-1α expression induced by IL-6. These results reveal the protective effects of FICZ on IL-6 induced disruption of intestinal epithelial barrier function through suppressing the expression of claudin-2. In addition, CDX-2 and HNF-1α are involved in the regulation of claudin-2 after IL-6 and FICZ treatment. Therefore compounds related to AhR ligands may be potential pharmaceutical agents to treat IBD.
Huang F Biomedicines. 2025; 12(12.
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Momen Y, Mishra J, Kumar N Nutrients. 2024; 16(15).
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Zhang J, Lin B, Zhang Y, Hu X, Liu T, Liu E Front Pharmacol. 2024; 15:1423307.
PMID: 38974042 PMC: 11224817. DOI: 10.3389/fphar.2024.1423307.
Wu X, Zhang Y, Ji M, Yang W, Deng T, Hou G Animals (Basel). 2024; 14(5).
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