Deoxynivalenol Impairs Porcine Intestinal Barrier Function and Decreases the Protein Expression of Claudin-4 through a Mitogen-Activated Protein Kinase-Dependent Mechanism

• Published in: The Journal of nutrition Vol. 140; no. 11; pp. 1956 - 1962
• Main Authors: Pinton, Philippe, Braicu, Cornelia, Nougayrede, Jean-Philippe, Laffitte, Joëlle, Taranu, Ionelia, Oswald, Isabelle P
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Nutrition 01.11.2010
• Subjects: animal models; animal proteins; Animals; biochemical pathways; Biological and medical sciences; Cell Line; cell lines; Cell Membrane Permeability - drug effects; Claudin-4; deoxynivalenol; Down-Regulation - drug effects; Electric Impedance; Enterocytes - drug effects; Enterocytes - metabolism; enzyme activation; Enzyme Activation - drug effects; enzyme inhibition; enzyme inhibitors; Enzyme Inhibitors - pharmacology; epithelial cells; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Feeding. Feeding behavior; Foodborne Diseases - physiopathology; Fundamental and applied biological sciences. Psychology; human nutrition; intestinal mucosa; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Life Sciences; Membrane Proteins - genetics; Membrane Proteins - physiology; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; permeability; phosphorylation; Phosphorylation - drug effects; Poisons - pharmacology; protein synthesis; RNA, Messenger - metabolism; Signal Transduction - drug effects; Swine; Tight Junctions - drug effects; Tight Junctions - metabolism; Toxicology; Toxicology and food chain; Trichothecenes - pharmacology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Nutrition; Digestive system; Enzyme; Barrier function; Transferases; Gut; Mitogen-activated protein kinase; Gene expression; Mechanism; Pig; Vertebrata; Mammalia; Decrease; Animal; Artiodactyla; Ungulata
• ISSN: 0022-3166; 1541-6100; 1541-6100
• DOI: 10.3945/jn.110.123919

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.