title: Deoxynivalenol impairs porcine intestinal barrier function and decreases the protein expression of claudin-4 through a mitogen-activated protein kinase-dependent mechanism.
abstract: Deoxynivalenol (DON) is a common mycotoxin that contaminates cereals and their by-products. The gastrointestinal tract is the first physical barrier against ingested food contaminants. DON contributes to the loss of barrier function of the intestine through the decreased expression of claudin-4 protein, a tight junction protein. The mechanism by which DON alters the intestinal barrier function remains poorly characterized. Therefore, we investigated the involvement of mitogen-activated protein kinases (MAPK) in the DON-induced loss of barrier function. We first verified that 30 μmol/L of DON activated MAPK in a highly sensitive porcine intestinal epithelial cell line (IPEC-1). Inhibition of p44/42 extracellular signal-regulated kinase (ERK) phosphorylation, with 0.5 μmol/L of the specific MAPK pharmacological inhibitor U0126 for 2 h, restored the barrier function of the differentiated intestinal epithelial cell monolayers. The restoration of barrier function was evaluated by trans-epithelial electrical resistance measurements and tracer flux paracellular permeability experiments. The U0126 also restored the intestinal expression of claudin-4 protein, thereby demonstrating that MAPK activation is involved in claudin-4 protein expression and claudin-4 is involved in the maintenance of the intestinal epithelial cell barrier function. Further experiments indicated that p44/42 ERK is not involved in the transcriptional regulation of claudin-4. In conclusion, we demonstrated that DON-induced activation of the p44/42 ERK signaling pathway inhibits the expression of claudin-4 protein, which leads to impaired intestinal barrier function. Given the high levels of DON in cereal grains, these observations of impaired barrier function have implications for human and animal health.
authors.affiliation: Laboratoire de Pharmacologie et Toxicologie UR66, INRA, F-31931 Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pinton
authors.forename: Cornelia
authors.initials: C
authors.lastname: Braicu
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Nougayrede
authors.forename: Joëlle
authors.initials: J
authors.lastname: Laffitte
authors.forename: Ionelia
authors.initials: I
authors.lastname: Taranu
authors.forename: Isabelle P
authors.initials: IP
authors.lastname: Oswald
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D062506:Claudin-4; D015536:Down-Regulation / Q000187:drug effects*; D017097:Electric Impedance; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005517:Foodborne Diseases / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011042:Poisons / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D014255:Trichothecenes / Q000494:pharmacology*
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011042:Poisons; D012333:RNA, Messenger; D014255:Trichothecenes; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C007262:deoxynivalenol