title: Both direct and indirect effects account for the pro-inflammatory activity of enteropathogenic mycotoxins on the human intestinal epithelium: stimulation of interleukin-8 secretion, potentiation of interleukin-1beta effect and increase in the transepithelial passage of commensal bacteria.
abstract: Mycotoxins are fungal secondary metabolites responsible of food-mediated intoxication in animals and humans. Deoxynivalenol, ochratoxin A and patulin are the best known enteropathogenic mycotoxins able to alter intestinal functions resulting in malnutrition, diarrhea, vomiting and intestinal inflammation in vivo. Although their effects on intestinal barrier and transport activities have been extensively characterized, the mechanisms responsible for their pro-inflammatory effect are still poorly understood. Here we investigated if mycotoxin-induced intestinal inflammation results from a direct and/or indirect pro-inflammatory activity of these mycotoxins on human intestinal epithelial cells, using differentiated Caco-2 cells as model and interleukin 8 (IL-8) as an indicator of intestinal inflammation. Deoxynivalenol was the only mycotoxin able to directly increase IL-8 secretion (10- to 15-fold increase). We also investigated if these mycotoxins could indirectly stimulate IL-8 secretion through: (i) a modulation of the action of pro-inflammatory molecules such as the interleukin-1beta (IL-1beta), and/or (ii) an increase in the transepithelial passage of non-invasive commensal Escherichia coli. We found that deoxynivalenol, ochratoxin A and patulin all potentiated the effect of IL-1beta on IL-8 secretion (ranging from 35% to 138% increase) and increased the transepithelial passage of commensal bacteria (ranging from 12- to 1544-fold increase). In addition to potentially exacerbate established intestinal inflammation, these mycotoxins may thus participate in the induction of sepsis and intestinal inflammation in vivo. Taken together, our results suggest that the pro-inflammatory activity of enteropathogenic mycotoxins is mediated by both direct and indirect effects.
authors.affiliation: Laboratoire des Interactions Moléculaires et Systèmes Membranaires (IMSM), Université Paul Cézanne, Faculté des Sciences et Techniques de Saint-Jérôme, Avenue Escadrille Normandie-Niemen, 13397, Marseille Cedex 20, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Maresca
authors.forename: Nouara
authors.initials: N
authors.lastname: Yahi
authors.forename: Lama
authors.initials: L
authors.lastname: Younès-Sakr
authors.forename: Marilyn
authors.initials: M
authors.lastname: Boyron
authors.forename: Bertrand
authors.initials: B
authors.lastname: Caporiccio
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
mesh_terms: D001419:Bacteria / Q000187:drug effects*; D018938:Caco-2 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology*; D009183:Mycotoxins / Q000633:toxicity*; D016328:NF-kappa B / Q000096:biosynthesis; D009793:Ochratoxins / Q000633:toxicity; D010365:Patulin / Q000633:toxicity; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014255:Trichothecenes / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D053583:Interleukin-1beta; D016209:Interleukin-8; D009183:Mycotoxins; D016328:NF-kappa B; D009793:Ochratoxins; D012333:RNA, Messenger; D014255:Trichothecenes; C025589:ochratoxin A; D010365:Patulin; D048051:p38 Mitogen-Activated Protein Kinases; C007262:deoxynivalenol