title: Gliadin intake alters the small intestinal mucosa in indomethacin-treated HLA-DQ8 transgenic mice.
abstract: Celiac disease (CD) is an enteropathy caused by the ingestion of wheat gluten in genetically susceptible individuals. A complete understanding of the pathogenic mechanisms in CD has been hindered because of the lack of adequate in vivo models. In the present study, we explored the events after the intragastric administration of gliadin and of the albumin/globulin fraction from wheat in human leukocyte antigen-DQ8 transgenic mice (DQ8 mice) treated with indomethacin, an inhibitor of cyclooxygenases (COXs). After 10 days of treatment, mice showed a significant reduction of villus height, increased crypt depth, increased number of lamina propria-activated macrophages, and high basal interferon-γ secretion in mesenteric lymph nodes, all of which were specifically related to gliadin intake, whereas the albumin/globulin fraction of wheat was unable to induce similar changes. Cotreatment with NS-398, a specific inhibitor of COX-2, also induced the intestinal lesion. Enteropathy onset was further characterized by high levels of oxidative stress markers, similar to CD. Biochemical assessment of the small intestine revealed the specific activation of matrix metalloproteinases 2 and 9, high caspase-3 activity, and a significant increase of tissue transglutaminase protein levels associated with the intestinal lesion. Notably, after 30 days of treatment, enteropathic mice developed serum antibodies toward gliadin (IgA) and tissue transglutaminase (IgG). We concluded that gliadin intake in combination with COX inhibition caused a basal inflammatory status and an oxidative stress condition in the small intestine of DQ8 mice, thus triggering the mucosal lesion and, subsequently, an antigen-specific immunity.
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mazzarella
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Bergamo
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Maurano
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Diomira
authors.initials: D
authors.lastname: Luongo
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Vera
authors.initials: V
authors.lastname: Rotondi Aufiero
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy;
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Bozzella
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy;
authors.forename: Gianna
authors.initials: G
authors.lastname: Palmieri
authors.affiliation: European Laboratory for Investigation of Food Induced Diseases and Department of Pediatrics, University "Federico II" of Naples, Naples, Italy; and.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Troncone
authors.affiliation: European Laboratory for Investigation of Food Induced Diseases and Department of Pediatrics, University "Federico II" of Naples, Naples, Italy; and.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Auricchio
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Chella
authors.initials: C
authors.lastname: David
authors.affiliation: Institute of Food Sciences, National Research Council, Avellino, Italy; mrossi@isa.cnr.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Rossi
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002446:Celiac Disease / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005903:Gliadin / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007213:Indomethacin / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009578:Nitrobenzenes / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013449:Sulfonamides / Q000633:toxicity; D013997:Time Factors; D011503:Transglutaminases / Q000276:immunology / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005903:Gliadin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D019204:GTP-Binding Proteins; D007213:Indomethacin
keywords: cyclooxygenases; enteropathy; gliadin; indomethacin; transgenic mice