TY - JOUR TI - Interleukin-28A Induces Epithelial Barrier Dysfunction in CD Patient-derived Intestinal Organoids AU - Xu, Pan AU - Becker, Heike AU - Elizalde, Montserrat AU - Pierik, Marieke AU - Masclee, Ad A.M. AU - Jonkers, Daisy M.A.E. T2 - American Journal of Physiology-Gastrointestinal and Liver Physiology AB - Intestinal barrier dysfunction is a pathogenic hallmark in Crohn's disease (CD). Identifying key players that regulate intestinal barrier may provide novel leads for therapeutic intervention. Interleukin-28A (IL-28A) is a newly identified IL-10/interferon cytokine family member, with its most implicated function being antiviral and anti-proliferative properties. However, the role and underlying mechanisms of IL-28A in the regulation of epithelial barrier in CD remain so far unexplored. IL-28A levels were measured in the plasma and biopsies of CD patients and healthy subjects. CD patient-derived intestinal organoids were characterized by differentiation gene markers and then exposed to TNF-α, IFN-γ, IL-1β or LPS, or IL-28A with or without GLPG0634 (filgotinib). Epithelial permeability was assessed by FITC-D4 flux. Expression of junctional components was analyzed by qRT-PCR, immunofluorescence staining or western blotting. JAK-STAT activity was analyzed by western blotting. IL-28A levels were increased in the plasma and biopsies from active CD patients as compared to healthy subjects. IL-28A and its receptor complex IL-28AR/IL-10R2 were detected in CD patient-derived intestinal organoids and showed a selective response to IFN-γ exposure. IL-28A triggered epithelial barrier disruption, accompanied by reduced ZO-1 and E-Cadherin expression. This effect was mediated by JAK-STAT1 pathway. Pre-incubation with the JAK1 inhibitor filgotinib ameliorated the barrier dysfunction induced by IL-28A. These results identified IL-28A as a novel regulator of epithelial barrier function and could be a putative target for CD treatment. We provide novel basic evidence that restoring intestinal barrier is a potential mechanism that contributes to the clinical benefits of JAK1 inhibitor in CD patients. DA - 2021/02/17/ PY - 2021 DO - 10.1152/ajpgi.00064.2020 DP - journals.physiology.org (Atypon) SN - 0193-1857 UR - https://journals.physiology.org/doi/abs/10.1152/ajpgi.00064.2020 Y2 - 2021/02/18/01:27:25 ER -