Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease
| Autor: | Marco Silano, Guido Kroemer, Valeria Raia, Manuela D’Eletto, Alice Castaldo, Mauro Piacentini, Romina Monzani, Gianni Bona, Antonella Tosco, Eleonora Ferrari, Speranza Esposito, Luigina Romani, Valeria Rachela Villella, Gian Luigi Marseglia, Alessandro Luciani, Luigi Maiuri, Federica Rossin |
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| Přispěvatelé: | Esposito, S, Villella, Vr, Ferrari, E, Monzani, R, Tosco, A, Rossin, F, D'Eletto, M, Castaldo, A, Luciani, A, Silano, M, Bona, G, Marseglia, Gl, Romani, L, Piacentini, M, Raia, V, Kroemer, G, Maiuri, L |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Aging Cystic Fibrosis Transmembrane Conductance Regulator Genistein Gliadin CFTR celiac disease genistein gluten peptides inflammation Ivacaftor Gene Knockout Techniques Mice chemistry.chemical_compound Gluten peptides Celiac disease Intestinal Mucosa Mice Inbred BALB C biology Chemistry food and beverages Inflammation Cell biology Female medicine.symptom Protein Binding Research Paper medicine.drug congenital hereditary and neonatal diseases and abnormalities Settore BIO/06 Models Biological digestive system Peripheral blood mononuclear cell Interferon-gamma Antigen Cell surface receptor medicine Animals Humans nutritional and metabolic diseases Cell Biology Potentiator Peptide Fragments digestive system diseases Disease Models Animal coeliac disease genistein CFTR Dietary Supplements biology.protein Caco-2 Cells |
| Zdroj: | Aging (Albany NY) |
| Popis: | In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD. |
| Databáze: | OpenAIRE |
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