title: Interleukin-33 suppresses Notch ligand expression and prevents goblet cell depletion in dextran sulfate sodium-induced colitis.
abstract: Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 plays an important role in Th2 immune responses, and induces goblet cell hyperplasia in the intestinal mucosa. In this study, to elucidate the molecular mechanisms underlying IL-33-induced goblet cell hyperplasia, we investigated how IL-33 modulates the Notch signaling pathway in dextran sulfate sodium (DSS)-induced experimental colitis. DSS colitis was induced in BALB/c mice with intraperitoneal administrations of IL-33 (1 µg/body) every 48 h. Tissue samples were evaluated by standard immunohistochemical procedures. The mucosal mRNA expression of the Notch ligands was analyzed by a real-time polymerase chain reaction. The mucosal mRNA expression of Notch ligands [Jagged1 (Jag1) and Delta-like (Dll) 1 and 4] was significantly increased in DSS-colitis mice. IL-33-induced goblet cell hyperplasia in the control mice. In the DSS-colitis mice, the goblet cells were depleted in the colon, but IL-33 completely prevented goblet cell depletion in the DSS-colitis mice. IL-33 induced a significant decrease in Jag1 and Dll4 mRNA expression in the mucosa of the control mice. Mucosal mRNA expression for Jag1, Dll1 and 4 was significantly elevated in the DSS-colitis mice, but this elevation was significantly blocked by the administration of IL-33. IL-33 dose-dependently decreased Jag1 mRNA expression in mouse colonic subepithelial myofibroblasts. In contrast to its preventive effects on goblet cell depletion, IL-33 aggravated DSS colitis. IL-33 prevented goblet cell depletion via its inhibitory actions against Notch ligand expression in DSS colitis, but exacerbated the disease activity. IL-33 plays two counter actions in mucosal inflammation; the first is a protective action via goblet cell induction, and the second is a pro-inflammatory action as a Th2 cytokine.
authors.affiliation: Department of Medicine, Graduate School of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Imaeda
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
authors.forename: Tomoki
authors.initials: T
authors.lastname: Aomatsu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Shigeki
authors.initials: S
authors.lastname: Bamba
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tsujikawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy*; D003106:Colon / Q000166:cytology / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity*; D020397:Goblet Cells / Q000187:drug effects*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000067596:Interleukin-33; D007378:Interleukins / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D060888:Real-Time Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; C506535:Il33 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000067596:Interleukin-33; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D016264:Dextran Sulfate