Format

Send to

Choose Destination
Aging (Albany NY). 2019 Apr 12;11(7):2003-2019. doi: 10.18632/aging.101888.

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease.

Author information

1
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan 20132, Italy.
2
Department of Health Sciences, University of Eastern Piedmont, Novara 28100, Italy.
3
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples 80131, Italy.
4
Department of Biology University of Rome "Tor Vergata", Rome 00133, Italy.
5
Institute of Physiology, University of Zurich, Zurich, 8057 Switzerland.
6
Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome 00161, Italy.
7
Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
8
Department of Experimental Medicine, University of Perugia, Perugia, 06123, Italy.
9
National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome 00149, Italy.
10
Senior co-authorship.
11
Equipe11 Labellisée Ligue Nationale Contrele Cancer, Centre de Recherche des Cordeliers, Paris 75006, France.
12
INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France.
13
Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris 75006, France.
14
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif 94805, France.
15
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France.
16
Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou 215123, China.
17
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
#
Contributed equally

Abstract

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.

KEYWORDS:

CFTR; celiac disease; genistein; gluten peptides; inflammation

PMID:
30981209
DOI:
10.18632/aging.101888
Free full text

Supplemental Content

Full text links

Icon for Impact Journals, LLC
Loading ...
Support Center