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-1β effect and increase in the transepithelial passage of commensal bacteria Marc Maresca a , Nouara Yahi a , Lama Younès-Sakr b , Marilyn Boyron a , Bertrand Caporiccio b , Jacques Fantini a, ⁎ a 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 b EA 3762 Nutrition-Aliments, Université Montpellier II, Place Eugène Bataillon, 34095, Montpellier Cedex 5, France Received 6 September 2007; revised 8 November 2007; accepted 12 November 2007 Available online 22 November 2007 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-1β), 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-1β 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. © 2008 Published by Elsevier Inc. Keywords: Enteropathogenic mycotoxin; Deoxynivalenol; Ochratoxin A; Patulin; Caco-2; Interleukin 8; Intestinal inflammation Introduction Mycotoxins are structurally unrelated secondary metabolites produced by fungi species belonging chiefly to three genera, i.e., Aspergillus, Penicillium and Fusarium (Bennett and Klich, 2003; Frisvad et al., 2006; Pitt et al., 2000). Intoxications by mycotoxins have been reported to result in alteration of bio- logical structures and functions of various tissues and systems. Thus, mycotoxins not only affect the intestinal, hepatic and/ or renal epithelia but also impact on the nervous, reproductive and immune systems (Al-Anati and Petzinger, 2006; Bondy and Pestka, 2000; Bouhet and Oswald, 2005; Campbell et al., 2004; Fuchs and Peraica, 2005; Fung and Clark, 2004; Oswald et al., 2005). In addition, carcinogenic and teratogenic effects of mycotoxins have been demonstrated (Clark and Snedeker, 2006; Pfohl-Leszkowicz and Manderville, 2007; Stark, 2005). Available online at www.sciencedirect.com Toxicology and Applied Pharmacology 228 (2008) 84 – 92 www.elsevier.com/locate/ytaap ⁎ Corresponding author. E-mail address: j.fantini@univ-cezanne.fr (J. Fantini). 0041-008X/$ - see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.taap.2007.11.013