title: The Food-Associated Ribotoxin Deoxynivalenol Modulates Inducible NO Synthase in Human Intestinal Cell Model.
abstract: The intestinal epithelium possesses active immune functions including the production of proinflammatory cytokines and antimicrobial molecules such as nitric oxide (NO). As observed with immune cells, the production of NO by the intestinal epithelium is mainly due to the expression of the inducible NO synthase (iNOS or NOS2). Epithelial immune functions could be affected by many factors including pathogenic microorganisms and food-associated toxins (bacterial and fungal). Among the various mycotoxins, deoxynivalenol (DON) is known to alter the systemic and intestinal immunity. However, little is known about the effect of DON on the production of NO by the intestinal epithelium. We studied the impact of DON on the intestinal expression of iNOS using the Caco-2 cell model. In line with its proinflammatory activity, we observed that DON dose-dependently up-regulates the expression of iNOS mRNA. Surprisingly, DON failed to increase the expression of iNOS protein. When testing the effects of DON on cytokine-mediated induction of iNOS, we found that very low concentrations of DON (ie, 1 µM) decrease the amount of iNOS protein but not of iNOS mRNA. We demonstrated that DON's effect on iNOS protein relies on its ability to activate signal pathways and to increase iNOS ubiquitinylation and degradation through the proteasome pathway. Taken together, our results demonstrate that although DON causes intestinal inflammation, it suppresses the ability of the gut epithelium to express iNOS and to produce NO, potentially explaining the increased susceptibility of animals to intestinal infection following exposure to low doses of DON.
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Graziani
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Ange
authors.initials: A
authors.lastname: Pujol
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Cendrine
authors.initials: C
authors.lastname: Nicoletti
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pinton
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Loriane
authors.initials: L
authors.lastname: Armand
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Di Pasquale
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Isabelle P
authors.initials: IP
authors.lastname: Oswald
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France.
authors.forename: Josette
authors.initials: J
authors.lastname: Perrier
authors.affiliation: *Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France, INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France, Université de Toulouse, INP, UMR1331, Toxalim, F-3100 Toulouse, France and Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344, Marseille, France m.maresca@univ-amu.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Maresca
mesh_terms: D018938:Caco-2 Cells; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004795:Enzyme Stability; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D005506:Food Contamination; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014255:Trichothecenes / Q000633:toxicity*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D014255:Trichothecenes; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex; C007262:deoxynivalenol
keywords: deoxynivalenol; iNOS; intestinal immunity; mycotoxin; nitric oxide; trichothecene