T-2 toxin inhibits the production of mucin via activating the IRE1/XBP1 pathway

• Published in: Toxicology (Amsterdam) 2019-08, Vol.424, p.152230-152230, Article 152230
• Main Authors: Lin, Ruqin, Sun, Yu, Ye, Wenchu, Zheng, Ting, Wen, Jikai, Deng, Yiqun
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Adhesion - drug effects; Caco-2 Cells; Cytokines - biosynthesis; E. coli O157:H7; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - drug effects; Endoribonucleases - metabolism; Enzyme Activation - drug effects; Escherichia coli O157 - drug effects; Gastrointestinal Microbiome - drug effects; HT29 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mucin; Mucin-2 - antagonists & inhibitors; Mucins - biosynthesis; Mycotoxin; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; T-2 toxin; T-2 Toxin - toxicity; X-Box Binding Protein 1 - agonists
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2019.06.001

•T-2 toxin activates the IRE1/XBP1 pathway to inhibit MUC2.•The expression of IRE1β is modulated by IRE1α.•IRE1α activation is a therapeutic target for intestinal inflammation caused by T-2 toxin.•T-2 toxin exposure increases E. coli O157:H7 susceptibility. T-2 toxin is a trichothecene mycotoxin that widely contaminates food and has a variety of toxic effects. However, the underlying mechanism of T-2 toxin on intestinal mucin remains unclear. In present study, human intestinal Caco-2 cells and HT-29 cells were treated with 100 ng/mL T-2 toxin at one-quarter of the IC50 for 24 h, which caused the inhibition of MUC2 and adhesion of E. coli O157:H7. We found T-2 toxin induced endoplasmic reticulum stress and activated the IRE1/XBP1 pathway, which may be related to the inhibition of MUC2. Interestingly, T-2 toxin activated IRE1α to inhibit IRE1β, which optimized mucin production. Furthermore, overexpression of IRE1β in the cells apparently alleviated the inhibition of MUC2 caused by T-2 toxin. IRE1α knock-down blocked the down-regulation of IRE1β and MUC2 induced by T-2 toxin. We revealed the critical role of IRE1α in the inhibition of intestinal mucin. This finding was confirmed in BALB/c mice which were exposed to T-2 toxin (0.5 mg/kg bw) for 4 weeks. T-2 toxin activated the IRE1/XBP1 pathway to disrupt intestinal mucin, which lead to the imbalance of gut microbiota and an increased risk of host infection by E. coli O157:H7. T-2 toxin exposure also increased the expressions of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in mice, which might respond to IRE1α activation. Importantly, IRE1α activation was a therapeutic target for intestinal inflammation caused by T-2 toxin. This study provided a new perspective to understand the intestinal toxicity of T-2 toxin.