Early Activation of MAPK p44/42 Is Partially Involved in DON-Induced Disruption of the Intestinal Barrier Function and Tight Junction Network.
Deoxynivalenol (DON), produced by the plant pathogens Fusarium graminearum and Fusarium culmorum, is one of the most common mycotoxins, contaminating cereal and cereal-derived products. Although worldwide contamination of food and feed poses health threats to humans and animals, pigs are particularly susceptible to this mycotoxin. DON derivatives, such as deepoxy-deoxynivalenol (DOM-1), are produced by bacterial transformation of certain intestinal bacteria, which are naturally occurring or applied as feed additives. Intestinal epithelial cells are the initial barrier against these food- and feed-borne toxins. The present study confirms DON-induced activation of MAPK p44/42 and inhibition of p44/42 by MAPK-inhibitor U0126 monoethanolate. Influence of DON and DOM-1 on transepithelial electrical resistance (TEER), viability and expression of seven tight junction proteins (TJ), as well as the potential of U0126 to counteract DON-induced effects, was assessed. While DOM-1 showed no effect, DON significantly reduced TEER of differentiated IPEC-J2 and decreased expression of claudin-1 and -3, while leaving claudin-4; ZO-1, -2, and -3 and occludin unaffected. Inhibition of p44/42 counteracted DON-induced TEER decrease and restored claudin-3, but not claudin-1 expression. Therefore, effects of DON on TEER and claudin-3 are at least partially p44/42 mediated, while effects on viability and claudin-1 are likely mediated via alternative pathways.
Biomin Research Center, Technopark 1, 3430 Tulln an der Donau, Austria. alexandra.springler@biomin.net.
Alexandra
A
Springler
Biomin Research Center, Technopark 1, 3430 Tulln an der Donau, Austria. sabine.hessenberger@biomin.net.
Sabine
S
Hessenberger
Biomin Research Center, Technopark 1, 3430 Tulln an der Donau, Austria. gerd.schatzmayr@biomin.net.
Gerd
G
Schatzmayr
Biomin Research Center, Technopark 1, 3430 Tulln an der Donau, Austria. e.mayer@biomin.net.
Elisabeth
E
Mayer
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013552:Swine; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014255:Trichothecenes / Q000633:toxicity*
D047428:Protein Kinase Inhibitors; D062725:Tight Junction Proteins; D014255:Trichothecenes; C048238:deepoxy-deoxynivalenol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C007262:deoxynivalenol
IPEC-J2; de-epoxy deoxynivalenol; deoxynivalenol; mycotoxin; tight junctions; transepithelial electrical resistance