{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T18:31:53Z","timestamp":1784831513397,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of this manuscript was to study the role of enterocytes in CD intestinal inflammation and their response to different proinflammatory factors, such as gliadin and viruses. Intestinal biopsies from CD patients on a gluten-containing (GCD-CD) or a gluten-free diet (GFD-CD) as well as biopsies from potential CD patients (Pot-CD) before the onset of intestinal lesions and controls (CTR) were used to investigate IL-1\u03b2 and IL-6 mRNA levels in situ. Organoids from CD patients were used to test the levels of NF-\u03baB, ERK, IL-6, and IL-1\u03b2 by Western blot (WB), ELISA, and quantitative PCR. The Toll-like receptor ligand loxoribine (Lox) and gliadin peptide P31-43 were used as proinflammatory stimuli. In CD biopsies inflammation markers IL-1\u03b2 and IL-6 were increased in the enterocytes, and also in Pot-CD before the onset of the intestinal lesion and in GFD-CD. The inflammatory markers pNF-\u03baB, pERK, IL-1\u03b2, and IL-6 were increased and persistent in CD organoids; these organoids were more sensitive to P31-43 and Lox stimuli compared with CTR organoids. Taken together, these observations point to constitutive inflammation in CD enterocytes, which are more sensitive to inflammatory stimuli such as food components and viruses.<\/jats:p>","DOI":"10.3390\/ijms23041973","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T02:35:51Z","timestamp":1644546951000},"page":"1973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Inflammation Is Present, Persistent and More Sensitive to Proinflammatory Triggers in Celiac Disease Enterocytes"],"prefix":"10.3390","volume":"23","author":[{"given":"Monia","family":"Porpora","sequence":"first","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Conte","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Lania","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-6776","authenticated-orcid":false,"given":"Claudia","family":"Bellomo","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Rapacciuolo","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7099-9142","authenticated-orcid":false,"given":"Fernando Gabriel","family":"Chirdo","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biologicas, Facultad de Ciencias Exactas, Instituto de Estudios Inmunologicos y Fisiopatologicos\u2014IIFP (UNLP-CONICET), Bv. 120 1489, La Plata 1900, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Auricchio","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Troncone","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Auricchio","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-4917","authenticated-orcid":false,"given":"Maria Vittoria","family":"Barone","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlin","family":"Nanayakkara","sequence":"additional","affiliation":[{"name":"ELFID (European Laboratory for the Investigation of Food Induced Diseases), Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/nri3407","article-title":"Triggers and drivers of autoimmunity: Lessons from coeliac disease","volume":"13","author":"Sollid","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Abenavoli, L., Dastoli, S., Bennardo, L., Boccuto, L., Passante, M., Silvestri, M., Proietti, I., Potenza, C., Luzza, F., and Nistic\u00f2, S.P. (2019). The Skin in Celiac Disease Patients: The Other Side of the Coin. Medicina, 55.","DOI":"10.3390\/medicina55090578"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-018-0054-z","article-title":"Coeliac disease","volume":"5","author":"Lindfors","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.aah5298","article-title":"Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease","volume":"356","author":"Bouziat","year":"2017","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.3390\/ijms151120518","article-title":"Gliadin peptides as triggers of the proliferative and stress\/innate immune response of the celiac small intestinal mucosa","volume":"15","author":"Barone","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.ircmb.2020.10.003","article-title":"The gliadin p31-43 peptide: Inducer of multiple proinflammatory effects","volume":"358","author":"Chirdo","year":"2021","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1084\/jem.20102660","article-title":"Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4","volume":"209","author":"Junker","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1053\/j.gastro.2018.02.024","article-title":"Dietary Patterns after the Weaning and Lactation Period Are Associated with Celiac Disease Autoimmunity in Children","volume":"154","author":"Barroso","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Barone, M.V., and Auricchio, S. (2021). A Cumulative Effect of Food and Viruses to Trigger Celiac Disease (CD): A Commentary on the Recent Literature. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042027"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41590-021-00869-6","article-title":"Inflammasomes and adaptive immune responses","volume":"22","author":"Deets","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2003526","DOI":"10.1002\/advs.202003526","article-title":"In Well-Treated Celiac Patients Low-Level Mucosal Inflammation Predicts Response to 14-day Gluten Challenge","volume":"8","author":"Stamnaes","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jcmgh.2020.07.010","article-title":"Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge","volume":"11","author":"Dotsenko","year":"2021","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/cr.2011.13","article-title":"NFkBin immunobiology","volume":"21","author":"Hayden","year":"2011","journal-title":"Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/gut.2008.169052","article-title":"Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling","volume":"58","author":"Trynka","year":"2009","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1093\/hmg\/ddt520","article-title":"Coregulation and modulation of NF\u03baB-related genes in celiac disease: Uncovered aspects of gut mucosal inflammation","volume":"23","author":"Irastorza","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/bs.ircmb.2017.07.003","article-title":"Profiling Celiac Disease-Related Transcriptional Changes","volume":"336","author":"Bilbao","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3389\/fimmu.2019.00420","article-title":"Disease-Associated SNPs in Inflammation-Related lncRNAs","volume":"10","author":"Ghosh","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s42003-019-0443-1","article-title":"Constitutive alterations in vesicular trafficking increase the sensitivity of cells from celiac disease patients to gliadin","volume":"2","author":"Lania","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Barone, M.V., Zanzi, D., Maglio, M., Nanayakkara, M., Santagata, S., Lania, G., Miele, E., Ribecco, M.T., Maurano, F., and Auricchio, R. (2011). Gliadin-mediated proliferation and innate immune activation in celiac disease are due to alterations in vesicular trafficking. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017039"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pietz, G., De, R., Hedberg, M., Sj\u00f6berg, V., Sandstr\u00f6m, O., Hernell, O., Hammarstr\u00f6m, S., and Hammarstr\u00f6m, M.L. (2017). Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185025"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2174\/138945008784221206","article-title":"Cytokines: From gut inflammation to colorectal cancer","volume":"9","author":"Fantini","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri1703","article-title":"NF-kappaB: Linking inflammation and immunity to cancer development and progression","volume":"5","author":"Karin","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.3389\/fimmu.2018.01270","article-title":"Cytokine Tuning of Intestinal Epithelial Function","volume":"9","author":"Andrews","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40348-015-0029-z","article-title":"Endocytosis and transcytosis of gliadin peptides","volume":"3","author":"Barone","year":"2016","journal-title":"Mol. Cell Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10821","DOI":"10.1038\/s41598-018-28830-y","article-title":"P31-43, an undigested gliadin peptide, mimics and enhances the innate immune response to viruses and interferes with endocytic trafficking: A role in celiac disease","volume":"8","author":"Nanayakkara","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7010","DOI":"10.1128\/IAI.68.12.7010-7017.2000","article-title":"Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease","volume":"68","author":"Cario","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1172\/JCI30587","article-title":"The fundamental basis of inflammatory bowel disease","volume":"117","author":"Strober","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a028415","DOI":"10.1101\/cshperspect.a028415","article-title":"Interleukin-6 Family Cytokines","volume":"10","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1053\/j.gastro.2020.05.064","article-title":"Ex Vivo Mimicking of Inflammation in Organoids Derived From Patients With Ulcerative Colitis","volume":"159","author":"Arnauts","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41575-020-00391-4","article-title":"Modelling intestinal inflammation and infection using \u2019mini-gut\u2019 organoids","volume":"18","author":"Li","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1038\/s41598-020-60521-5","article-title":"Intestinal ex vivo organoid culture reveals altered programmed crypt stem cells in patients with celiac disease","volume":"10","author":"Dieterich","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2174\/1871530319666191116141159","article-title":"Interleukin 1-beta is Linked to Chronic Low-Grade Inflammation and Cardiovascular Risk Factors in Overweight Adolescents","volume":"20","author":"Amaral","year":"2020","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1038\/s41598-019-43426-w","article-title":"Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease","volume":"9","author":"Freire","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Galatola, M., Izzo, V., Cielo, D., Morelli, M., Gambino, G., Zanzi, D., Strisciuglio, C., Sperandeo, M.P., Greco, L., and Auricchio, R. (2013). Gene expression profile of peripheral blood monocytes: A step towards the molecular diagnosis of celiac disease?. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074747"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14303","DOI":"10.1038\/s41598-019-50735-7","article-title":"A Phospholipid Profile at 4 Months Predicts the Onset of Celiac Disease in at-Risk Infants","volume":"9","author":"Auricchio","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1136\/archdischild-2019-317976","article-title":"Growth rate of coeliac children is compromised before the onset of the disease","volume":"105","author":"Auricchio","year":"2020","journal-title":"Arch. Dis. Child."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1365-2249.2008.03743.x","article-title":"Higher constitutive IL15R alpha expression and lower IL-15 response threshold in coeliac disease patients","volume":"154","author":"Bernardo","year":"2008","journal-title":"Clin. Exp. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jcmgh.2017.02.011","article-title":"Self-renewing Monolayer of Primary Colonic or Rectal Epithelial Cells","volume":"4","author":"Wang","year":"2017","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"Sato","year":"2009","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1136\/gutjnl-2013-306651","article-title":"Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays","volume":"64","author":"VanDussen","year":"2015","journal-title":"Gut"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:17:50Z","timestamp":1760134670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/1973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,10]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23041973"],"URL":"https:\/\/doi.org\/10.3390\/ijms23041973","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,10]]}}}